Bicyclic AZA compounds as muscarinic M1 receptor and/or M4 receptor

ABSTRACT

This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1, or a salt thereof, wherein Q, R 1 , R 2 , R 3  and R 4  are as defined herein.

This application is a continuation of U.S. patent application Ser. No.16/459,179, filed on Jul. 1, 2019, which is a continuation of U.S.patent application Ser. No. 16/217,570, filed on Dec. 12, 2018, now U.S.Pat. No. 10,385,039, which is a continuation of U.S. patent applicationSer. No. 15/902,537, filed on Feb. 22, 2018, now U.S. Pat. No.10,196,380, which is a continuation of U.S. patent application Ser. No.15/591,605, filed on May 10, 2017, now U.S. Pat. No. 9,926,297, which isa continuation of U.S. patent application Ser. No. 15/117,018, filed onAug. 5, 2016, now U.S. Pat. No. 9,670,183, which is a 371 ofInternational Patent Application PCT/GB2015/050331, filed on Feb. 6,2015, which claims priority from GB Patent Application No.: 1416622.7,filed on Sep. 19, 2014 and from GB Patent Application No.: 1402013.5,filed on Feb. 6, 2014. The entire contents of these applications areincorporated herein by reference in their entirety.

This invention relates to compounds that are agonists of the muscarinicM1 receptor and/or M4 receptor and which are useful in the treatment ofmuscarinic M1/M4 receptor mediated diseases. Also provided arepharmaceutical compositions containing the compounds and the therapeuticuses of the compounds.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead at al., 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead at al, 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse at al., 1982 Science). In schizophrenia, whichalso has cognitive impairment as an important component of the clinicalpicture, mAChR density is reduced in the pre-frontal cortex, hippocampusand caudate putamen of schizophrenic subjects (Dean at al., 2002 MolPsychiatry). Furthermore, in animal models, blockade or damage tocentral cholinergic pathways results in profound cognitive deficits aidnon-selective mAChR antagonists have been shown to inducepsychotomimetic effects in psychiatric patients. Cholinergic replacementtherapy has largely been based on the use of acetylcholinesteraseinhibitors to prevent the breakdown of endogenous acetylcholine. Thesecompounds have shown efficacy versus symptomatic cognitive decline inthe clinic, but give rise to dose-limiting adverse events resulting fromstimulation of peripheral M₂ and M₃ mAChRs including disturbedgastrointestinal motility, bradycardia, nausea and vomiting(http://www.drugs.com/pro/donepezil.html;http://www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists with the aim of inducing selective improvements incognitive function with a favourable adverse effect profile. Suchefforts resulted in the identification of a range of agonists,exemplified by compounds such as xanomeline, AF267B, sabcomeline,milameline and cevimeline. Many of these compounds have been shown to behighly effective in pre-clinical models of cognition in both rodentsand/or non-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain pathologies: aggregates of amyloid plaques, largelycomposed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formedby hyperphosphorylated tau proteins. The accumulation of Aβ is thoughtto be the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. Aβ is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, nonamyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. However, in the amyloidgenicroute, APP is cleaved by β-secretase to yield soluble APPβ and also Aβ.In vitro studies have shown that mAChR agonists can promote theprocessing of APP toward the soluble, non-amyloidogenic pathway. In vivostudies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron). ThemAChR agonist cevimeline has been shown to give a small, butsignificant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Preclinical studies have suggested that mAChR agonists display anatypical antipsychotic-like profile in a range of pre-clinicalparadigms. The mAChR agonist, xanomeline, reverses a number of dopaminemediated behaviours, including amphetamine induced locomotion in rats,apomorphine induced climbing in mice, dopamine agonist driven turning inunilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest inmonkeys (without EPS liability). It also has been shown to inhibit A10,but not A9, dopamine cell firing and conditioned avoidance and inducesc-fos expression in prefrontal cortex and nucleus accumbens, but not instriatum in rats. These data are all suggestive of an atypicalantipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev). Muscarinicreceptors have also been implicated in the neurobiology of addiction.The reinforcing effects of cocaine and other addictive substances aremediated by the mesolimbic dopamine system where behavioral andneurochemical studies have shown that the cholinergic muscarinicreceptor subtypes play important roles in regulation of dopaminergicneurotransmission. For example M(4) (−/−) mice demonstratedsignificantly enhanced reward driven behaviour as result of exposure tococaine (Schmidt et al Psychopharmacology (2011) August; 216(3):367-78).Furthermore xanomeline has been demonstrated to block the effects ofcocaine in these models.

Muscarinic receptors are also involved in the control of movement andpotentially represent novel treatments for movement disorders such asParkinson's disease. ADHD, Huntingdon's disease, tourette's syndrome andother syndromes associated with dopaminergic dysfunction as anunderlying pathogenetic factor driving disease.

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1967 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic adverse events, including nausea, gastrointestinal pain,diahorrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damage;however management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M1 receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson et al., 2010 Bioorg Med Chem Lett, Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ and/or M₄ mAChR over the M₂ and M₃ receptorsubtypes.

DESCRIPTION OF FIGURES

Description of the figures can be found in experimental sections B and C

FIG. 1 shows that Example 1-33 Isomer 2 was found to reversescopolamine-induced amnesia in a dose-dependent manner, with anapproximate ED₅₀ of ca. 10 mg/kg (po). The effect of 30 mg/kg wassimilar to that produced by the cholinesterase inhibitor donepezil (0.1mg/kg, ip) which served as a positive control.

FIG. 2 shows the effect of novel test compounds on d-amphetamine inducedhyperactivity in rats. Antipsychotic-like behaviour was assessed in ratsby the inhibition of hyperactivity (or hyperlocomotion) elicited byd-amphetamine. Data for Examples 1-21 Isomer 2, 1-32 Isomer 2, 1-33Isomer 2, 2-7 Isomer 2 and 2-17 Isomer 2 is shown.

THE INVENTION

The present invention provides compounds having activity as muscarinicM1 and/or M4 receptor agonists. More particularly, the inventionprovides compounds that exhibit selectivity for the M1 receptor and/orthe M4 receptor relative to the M2 and M3 receptor subtypes.

Accordingly, in one embodiment (Embodiment 1.1), the invention providesa compound of the formula (1):

or a salt thereof, wherein

Q is a five or six membered monocyclic heterocyclic ring containing 1,2, 3 or 4 heteroatom ring members selected from N, O and S;

R¹ is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo;hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁶ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof, and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

R² is selected from hydrogen; fluorine; chlorine; bromine; cyano;hydroxy; methoxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶;NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁵; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatichydrocarbon group; or R¹ and R² can be joined together to form a 6membered fused aromatic ring;

R³ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁴ is a hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof;

R⁵, R⁶ and R⁷ are the same or different and each is independentlyselected from hydrogen, a non-aromatic C₁₋₄ hydrocarbon group optionallysubstituted with one or more fluorine atoms; or a group of formulaCH₂N(R^(a))COOR^(b);

R^(a) is selected from hydrogen and a non-aromatic C₁₋₄ hydrocarbongroup;

R^(b) is a non-aromatic C₁₋₄ hydrocarbon group which is optionallysubstituted with one or more groups selected from fluorine; chlorine;bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl,heterocycloalkyl, aryl or heteroaryl group;

-   -   and the dotted line indicates an optional second carbon-carbon        bond, provided that when a second carbon-carbon bond is present,        then R³ is absent.

Accordingly, in one embodiment (Embodiment 1.1a), the invention providesa compound of the formula (1a).

or a salt thereof, wherein

Q is a five or six or seven membered monocyclic heterocyclic ringcontaining 1, 2, 3 or 4 heteroatom ring members selected from N, O andS;

R¹ is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo;hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof, and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

R² is selected from hydrogen; fluorine; chlorine; bromine; cyano;hydroxy; methoxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶;NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁵; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatichydrocarbon group; or R¹ and R² can be joined together to form a 6membered fused aromatic ring;

R¹ is selected from hydrogen; fluorine; cyano; hydroxy, amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁴ is a hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof;

R⁵, R⁶ and R⁷ are the same or different and each is independentlyselected from hydrogen, a non-aromatic C₁₋₄ hydrocarbon group optionallysubstituted with one or more fluorine atoms; or a group of formulaCH₂N(R^(a))COOR^(b);

R^(a) is selected from hydrogen and a non-aromatic C₁₋₄ hydrocarbongroup;

R^(b) is a non-aromatic C₁₋₄ hydrocarbon group which is optionallysubstituted with one or more groups selected from fluorine; chlorine,bromine; cyano, hydroxy, methoxy, amino; or a cycloalkyl,heterocycloalkyl, aryl or heteroaryl group;

and the dotted line indicates an optional second carbon-carbon bond,provided that when a second carbon-carbon bond is present then R³ isabsent.

Accordingly, in one embodiment (Embodiment 1.1b), the invention providesa compound of the formula (1b):

or a salt thereof, wherein

Q is an optionally substituted five or six or seven memberedheterocyclic ring containing 1, 2, 3 or 4 heteroatom ring membersselected from N, O and S;

R³ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof;

R⁴ is a hydrogen or a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidised formsthereof;

and the dotted line indicates an optional second carbon-carbon bond,provided that when a second carbon-carbon bond is present, then R³ isabsent.

Particular compounds of the formula (1), (1a) or (1b) are as defined inthe Embodiments 1.2 to 1.180 set out below.

1.2 A compound according to Embodiment 1.1 wherein Q is an aromatic orunsaturated heterocyclic ring.

1.3 A compound according to Embodiment 1.2 wherein Q is an aromaticheterocyclic ring.

1.4 A compound according to Embodiment 1.3 wherein Q is an aromaticheterocyclic ring containing a nitrogen ring member and optionally oneor two further ring members selected from O, N and S.

1.5 A compound according to Embodiment 1.4 wherein Q is an aromaticheterocyclic ring containing a nitrogen ring member and optionally onefurther ring member selected from O, N and S.

1.6 A compound according to Embodiment 1.5 wherein Q is an aromaticheterocyclic ring containing one or two nitrogen ring members.

1.7 A compound according to any one of Embodiments 1.1 to 1.6 wherein Qis a five membered heterocyclic ring linked to the adjacent six-memberedring by a carbon atom of the said five membered heterocyclic ring.

1.8 A compound according to any one of Embodiments 1.1 to 1.6 wherein Qis a five membered heterocyclic ring linked to the adjacent six-memberedring by a nitrogen atom of the said five membered heterocylic ring.

1.9 A compound according to Embodiment 1.1 wherein Q is selected from1-pyrrolyl, 2-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl,2-thiazolyl, 2-oxazolyl, triazolyl, tetrazolyl, thiadiazolyl,oxadiazolyl, and tautomeric forms thereof.

1.10 A compound according to Embodiment 1.6 wherein Q is a pyrrole ring.

1.11 A compound according to Embodiment 1.6 wherein Q is an imidazolering

1.12 A compound according to Embodiment 1.6 wherein Q is a pyrazolering.

1.13 A compound according to Embodiment 1.6 wherein Q is selected from1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl and tautomeric forms thereof.

1.14 A compound according to Embodiment 1.1 wherein Q is a 6 memberedring containing one or more nitrogen atoms.

1.15 A compound according to Embodiment 1.14 wherein Q is pyridyl,pyrazyl or a 2-oxo-3N (3-piperidin-2-one) ring containing 0-2 C—Cunsaturated bonds.

1.16 A compound according to Embodiment 1.1 wherein Q is a 5, 6 or 7membered unsaturated heterocyclic ring.

1.17 A compound according to Embodiment 1.16 wherein Q is5-pyrollidinyl.

1.18 A compound according to Embodiment 1.1 wherein Q is bicyclic;having a further ring attached to Q.

1.19 A compound according to Embodiment 1.1b wherein Q has one or moresubstituents, for example one, two or three substituents, which may beselected from one R¹ and/or R² wherein R¹ and R² may be the same ordifferent. Further substituents for Q may include (L)-R¹⁰, (L)-R¹¹ and(L)-R¹², where L is a bond or a GHz group; R¹⁰, R¹¹ and R¹² areindependently selected from hydrogen; fluorine; chlorine; bromine;cyano; oxo; hydroxy; OR¹⁵; NR¹⁵R¹⁶; COR¹⁵; CSR¹⁵; COOR¹⁵; COSR¹⁵;OCOR¹⁵; NR¹⁷COR¹⁵; CONR¹⁵R¹⁶; CSNR¹⁵R¹⁶; NR¹⁷CONR¹⁶R¹⁶; R¹⁷COOR¹⁵;OCONR¹⁵R¹⁶; SR¹⁵; SOR¹⁵ and SO₂R¹⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof; and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 8-membered ring are selected from a group R⁸ consisting of        hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;        NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁶; NR⁷COOR⁵;        OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof;    -   wherein R¹⁵, R¹⁶ and R¹⁷ are the same or different, or may be        joined together to form a ring, and each is independently        selected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group        optionally substituted with one or more fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidized forms thereof; or a group of formula        CH₂N(R^(a))COOR^(b); or a group of formula (L)-R¹⁸ where L is a        bond or a CH₂ group and R¹⁸ is an optionally substituted 5- or        6-membered ring containing 0, 1, 2 or 3 heteroatoms selected        from O, N and S and oxidized forms thereof;    -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸.

1.20 A compound according to any one of Embodiments 1.1 to 1.19 whereinR¹ is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo;hydroxy; OR⁵; NR⁶R⁶; COR⁵, COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbongroup which is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof; and an optionally substituted 5- or 6-memberedring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S andoxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸ consisting of        hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;        NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁸,        NR⁷COOR⁵, OCONR⁵R⁶; SR⁵, SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof.

1.21 A compound according to Embodiment 1-20 wherein R¹ is selected fromhydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶;SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered ring containing0, 1 or 2 heteroatoms selected from O, N and S and oxidized formsthereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁶ consisting of        fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;        COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁸; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵;        OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof.

1.22 A compound according to Embodiment 121 wherein R¹ is selected fromhydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶;COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶;SR⁵; SOR⁵ and SO₂R⁵; a C₁₋₄ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered aryl orheteroaryl ring containing 0, 1 or 2 heteroatoms selected from O, N andS and oxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered aryl or heteroaryl ring are selected from a        group R⁸ consisting of fluorine; chlorine; bromine; cyano; oxo;        hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶;        NR⁷CONR⁵R⁶; NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄        non-aromatic hydrocarbon group which is optionally substituted        with one to six fluorine atoms and wherein one or two, but not        all, carbon atoms of the hydrocarbon group may optionally be        replaced by a heteroatom selected from O, N and S and oxidized        forms thereof.

1.23 A compound according to any one of Embodiments 1.1 to 1.19 whereinR¹ is selected from hydrogen; fluorine; chlorine; cyano; oxo; hydroxy,OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁶;OCONR⁵R⁶; SO₂R⁵; a C₁₋₄ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not ail, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof; and an optionally substituted 5- or 6-membered ring containing0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized formsthereof, wherein the optional substituents for the optionallysubstituted 5- or 6-membered ring are selected from a group R⁸consisting of fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;NR⁶R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵;OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₄ non-aromatic hydrocarbon groupwhich is optionally substituted with one to six fluorine atoms andwherein one or two, but not all, carbon atoms of the hydrocarbon groupmay optionally be replaced by a heteroatom selected from O, N and S andoxidized forms thereof.

1.24 A compound according to Embodiment 1.23 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; hydroxy; OR⁵; NR⁶R⁶; COR⁵; COOR⁵;OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁵; NR⁷COOR⁵; OCONR⁵R⁶; SO_(Z)R⁵; and aC₁₋₄ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one or two, but not all, carbonatoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof.

1.25 A compound according to Embodiment 1.24 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵;OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶; NR⁷COOR⁵; SO₂R⁵; and a C₁₋₄non-aromatic hydrocarbon group which is optionally substituted with oneto six fluorine atoms.

1.26 A compound according to Embodiment 1.25 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; NR⁵R⁶; COR⁵; COOR⁵ and a C₁₋₆non-aromatic hydrocarbon group which is optionally substituted with oneto six fluorine atoms.

1.27 A compound according to Embodiment 1.26 wherein R¹ is selected fromhydrogen; fluorine; chlorine; cyano; NH₂, COR⁵; COOR⁵ and a C₁₋₄saturated non-aromatic hydrocarbon group which is optionally substitutedwith one to six fluorine atoms.

1.28 A compound according to Embodiment 1.27 wherein R¹ is selected fromhydrogen; COR⁵; COOR⁵; CONR⁵R⁶ and a C₁₋₄ alkyl group.

1.29 A compound according to Embodiment 1.28 wherein R¹ is selected fromhydrogen; COR⁵; COOR⁵ and a C₁₋₃ alkyl group.

1.30 A compound according to Embodiment 1.29 wherein R¹ is selected fromhydrogen; methyl; ethyl and COOR⁵.

1.31 A compound according to Embodiment 1.30 wherein R¹ is hydrogen.

1.32 A compound according to Embodiment 1.30 wherein R¹ is methyl orethyl.

1.33 A compound according to Embodiment 1.20 to 1.30 wherein R¹ isCOOMe; COOEt; COMe; COEt; CONH₂; CF₃; CONHMe; CON(Me)₂; COCF₃;CO-cyclopropyl; CO-cyclobutyl; CONHEt; COH; NH₂; OMe;

1.34 A compound according to any one of the Embodiments 1.1 to 1.33wherein R² is selected from hydrogen; fluorine; chlorine; bromine;cyano; hydroxy; methoxy; and a C₁₋₆ non-aromatic hydrocarbon group; oris joined together with R¹ to form a 6 membered fused aromatic ring.

1.35 A compound according to Embodiment 1.34 wherein R² is selected fromhydrogen; fluorine; hydroxy; methoxy; and a C₁₋₆ non-aromatichydrocarbon group.

1.36 A compound according to Embodiment 1.35 wherein R² is selected fromhydrogen; fluorine; methoxy; and a C₁₋₄ saturated hydrocarbon group.

1.37 A compound according to Embodiment 1.36 wherein R² is selected fromhydrogen; fluorine; methoxy; and a C₁₋₄ alkyl group.

1.38 A compound according to Embodiment 1.37 wherein R² is selected fromhydrogen and a C₁₋₃ alkyl group.

1.39 A compound according to Embodiment 1.38 wherein R² is selected fromhydrogen and methyl.

1.40 A compound according to Embodiment 1.34 wherein R² is joinedtogether with R¹ to form a 6 membered fused aromatic ring which may bearyl or heteroaryl.

1.41 A compound according to any one of Embodiments 1.1 to 1.40 whereinthe dotted line represents a second carbon-carbon bond and R³ is absent.

1.42 A compound according to any one of Embodiments 1.1 to 1.40 whereinR¹ is present and the optional second carbon-carbon bond is absent.

1.43 A compound according to Embodiment 1.42 wherein R¹ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; and a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one or two, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof.

1.44 A compound according to Embodiment 1.43 wherein R³ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; and a C₁₋₆ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms and wherein one, but not all, carbon atoms of thehydrocarbon group may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidized forms thereof.

1.45 A compound according to Embodiment 1.44 wherein R³ is selected fromhydrogen; fluorine; cyano; hydroxy; amino; C₁₋₄ alkyl and C₁₋₄ alkoxy,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith one to six fluorine atoms.

1.46 A compound according to Embodiment 1.45 wherein R³ is selected fromhydrogen; fluorine; hydroxy and methoxy.

1.47 A compound according to Embodiment 1.46 wherein R¹ is hydrogen.

1.48 A compound according to any one of Embodiments 1.1 to 1.47 whereinR⁴ is hydrogen or an acyclic C₁₋₄ hydrocarbon group.

1.49 A compound according to Embodiment 1.48 wherein R⁴ is hydrogen oran acyclic C₁₋₃ hydrocarbon group.

1.50 A compound according to Embodiment 1.49 wherein R⁴ is hydrogen or aC₁₋₃ alkyl group or a C₂₋₃ alkynyl group.

1.51 A compound according to Embodiment 1.50 wherein R⁴ is selected fromhydrogen, methyl, ethyl, ethynyl and 1-propynyl.

1.52 A compound according to Embodiment 1.51 wherein R⁴ is selected fromhydrogen and methyl.

1.53 A compound according to Embodiment 1.52 wherein R⁴ is methyl.

1.54 A compound according to any one of the preceding Embodimentswherein R⁵, when present, is a non-aromatic C₁₋₄ hydrocarbon groupoptionally substituted with one or more fluorine atoms; or a group offormula CH₂N(R^(a))COOR^(b).

1.55 A compound according to Embodiment 1.54 wherein the non-aromaticC₁₋₄ hydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.56 A compound according to any one of Embodiments 1.1 to 1.53 whereinR⁵, when present is hydrogen.

1.57 A compound according to any one of Embodiments 1.1 to 1.53 whereinR⁵, when present is selected from hydrogen and a saturated C₁₋₄hydrocarbon group.

1.58 A compound according to Embodiment 1.55 or Embodiment 1.56 whereinthe saturated C₁₋₄ hydrocarbon group is a C₁₋₄ alkyl group.

1.59 A compound according to Embodiment 1.58 wherein the saturated C₁₋₄hydrocarbon group is a C₁₋₃ alkyl group.

1.60 A compound according to Embodiment 1.59 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.61 A compound according to Embodiment 1.60 wherein the C₁₋₃ alkylgroup is ethyl.

1.62 A compound according to any one of the preceding Embodimentswherein R⁶, when present, is a non-aromatic C₁₋₄ hydrocarbon group.

1.63 A compound according to Embodiment 1.62 wherein the non-aromaticC₁₋₄ hydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.64 A compound according to any one of Embodiments 1.1 to 1.61 whereinR⁵, when present, is hydrogen.

1.65 A compound according to Embodiment 1.63 wherein the saturated CMhydrocarbon group is a C₁₋₃ alkyl group.

1.66 A compound according to Embodiment 1.65 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.67 A compound according to any one of the preceding Embodimentswherein R⁷, when present, is a non-aromatic C₁₋₄ hydrocarbon group.

1.68 A compound according to Embodiment 1.67 wherein the non-aromatic CMhydrocarbon group is a saturated C₁₋₄ hydrocarbon group.

1.69 A compound according to any one of Embodiments 1.1 to 1.66 whereinR⁷, when present is hydrogen.

1.70 A compound according to any one of Embodiments 1.1 to 1.66 whereinR⁷, when present is selected from hydrogen and a saturated C₁₋₄hydrocarbon group.

1.71 A compound according to Embodiment 1.68 or Embodiment 1.70 whereinthe saturated C₁₋₄ hydrocarbon group is a C₁₋₄ alkyl group.

1.72 A compound according to Embodiment 1.71 wherein the saturated CMhydrocarbon group is a C₁₋₃ alkyl group.

1.73 A compound according to Embodiment 1.72 wherein the C₁₋₃ alkylgroup is selected from methyl, ethyl and isopropyl.

1.74 A compound according to any one of the preceding Embodimentswherein, when R¹ is an optionally substituted 5- or 6-membered ring, itis selected from aromatic rings containing 0, 1 or 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof.

1.75 A compound according to Embodiment 1.74 wherein the aromatic ringis carbocyclic.

1.76 A compound according to Embodiment 1.74 wherein the aromatic ringis heterocyclic.

1.77 A compound according to any one of Embodiments 1.1 to 1.73 wherein,when R¹ is an optionally substituted 5- or 6-membered ring, it isselected from non-aromatic rings containing 0, 1 or 2 or 3 heteroatomsselected from O, N and S and oxidized forms thereof.

1.78 A compound according to Embodiment 1.77 wherein the non-aromaticring is carbocyclic.

1.79 A compound according to Embodiment 1.77 wherein the non-aromaticring is heterocyclic.

1.80 A compound according to any one of Embodiments 1.74 to 1.79 whereinthe ring is a 5-membered ring.

1.81 A compound according to any one of Embodiments 1.74 to 1.79 whereinthe ring is a 6-membered ring.

1.82 A compound according to any one of the preceding Embodimentswherein, when R¹ is an optionally substituted 5- or 6-membered ring, itis substituted with 0, 1, 2 or 3 substituents R⁸.

1.83 A compound according to Embodiment 1.82 wherein there are 0, 1 or 2substituents R⁸ present.

1.84 A compound according to Embodiment 1.83 wherein there are 0substituents R⁸ present.

1.85 A compound according to Embodiment 1.82 wherein there is 1substituent R⁸ present.

1.86 A compound according to Embodiment 1.82 wherein there are 2substituents R⁸ present.

1.87 A compound according to any one of Embodiments 1.81, 1.82, 1.83,1.85 and 1.86 wherein R⁸ when present is selected from fluorine; cyano;oxo; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁶; CONR⁵R⁶; SR⁵;SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic hydrocarbon group which isoptionally substituted with one to six fluorine atoms and wherein one ortwo, but not all, carbon atoms of the hydrocarbon group may optionallybe replaced by a heteroatom selected from O, N and S and oxidized formsthereof.

1.88 A compound according to Embodiment 1.87 wherein R⁸ is selected fromfluorine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵ and SO₂R⁸;and a C₁₋₄ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidized formsthereof.

1.89 A compound according to Embodiment 1.88 wherein R⁸ is selected fromfluorine; cyano; oxo; hydroxy; OR⁵; NR⁵R⁶; and a C₁₋₄ non-aromatichydrocarbon group which is optionally substituted with one to sixfluorine atoms.

1.90 A compound according to Embodiment 1.89 wherein R⁸ is selected fromcyano; oxo; hydroxy; OR⁵; NR⁵R⁶; and C₁₋₄ alkyl.

1.91 A compound according to any one of Embodiments 1.1 to 1.40 and 1.42to 1.53 wherein the moiety:

is selected from groups AAA to ACB below:

1.92 A compound according to having the formula (2) or formula 2a:

wherein Q is an optionally substituted 5 or 6 membered heterocyclic orheteraryl ring have one or more nitrogen atoms, and R⁴ is as defined inany one of Embodiments 1.48 to 1.53; or

wherein Q is an optionally substituted 5, 6 or 7 membered heterocyclicor heteraryl ring have one or more nitrogen atoms, and R⁴ is as definedin any one of Embodiments 1.48 to 1.53.

1.93 A compound according to formula (2) or formula (2a) wherein Q hasone or more substituents, for example one, two or three substituentswhich are selected from (L)-R¹⁰, (L)-R¹¹ and (L)-R¹², where L is a bondor a CH₂ group, R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR¹⁵;NR¹⁵R¹⁶; COR¹⁵; CSR¹⁵; COOR¹⁵; COSR¹⁵; OCOR¹⁵; NR¹⁷COR¹⁵; CONR¹⁵R¹⁶;CSNR¹⁵R¹⁶; NR¹⁷CONR¹⁵R¹⁶; R¹⁷COOR¹⁵; OCONR¹⁵R¹⁶; SR¹⁵; SOR¹⁵ and SO₂R¹⁵;a C₁₋₈ non-aromatic hydrocarbon group which is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof; and anoptionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3heteroatoms selected from O, N and S and oxidized forms thereof;

-   -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸ consisting of        hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR⁵;        NR⁵R⁶; COR⁵; COOR⁵; OCOR⁵; NR⁷COR⁵; CONR⁵R⁶; NR⁷CONR⁵R⁶;        NR⁷COOR⁵; OCONR⁵R⁶; SR⁵; SOR⁵ and SO₂R⁵; and a C₁₋₆ non-aromatic        hydrocarbon group which is optionally substituted with one to        six fluorine atoms and wherein one or two, but not all, carbon        atoms of the hydrocarbon group may optionally be replaced by a        heteroatom selected from O, N and S and oxidized forms thereof;    -   wherein R¹⁵, R¹⁶ and R¹⁷ are the same or different, or may be        joined together to form a ring, and each is independently        selected from hydrogen, a non-aromatic C₁₋₆ hydrocarbon group        optionally substituted with one or more fluorine atoms and        wherein one or two, but not all, carbon atoms of the hydrocarbon        group may optionally be replaced by a heteroatom selected from        O, N and S and oxidized forms thereof; or a group of formula        CH₂N(R⁸)COOR^(b); or a group of formula (L)-R¹⁸ where L is a        bond or a CH₂ group and R¹⁸ is an optionally substituted 5- or        6-membered ring containing 0, 1, 2 or 3 heteroatoms selected        from O, N and S and oxidized forms thereof;    -   wherein the optional substituents for the optionally substituted        5- or 6-membered ring are selected from a group R⁸.

1.94 A compound according to Embodiments 1.1 to 1.93 having the formula(3):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90 and the ring A is a five membered heterocyclic orheteroaryl ring containing one or two nitrogen ring members.

1.95 A compound according to Embodiment 1.94 wherein the ring A is afive membered heteroaryl ring containing two nitrogen ring members.

1.96 A compound according to Embodiment 1.95 wherein the ring A is animidazole ring.

1.97 A compound according to Embodiment 1.96 having the formula (4):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90.

1.98 A compound according to Embodiment 1.95 wherein the ring A is apyrazole ring.

1.99 A compound according to Embodiment 1.98 having the formula (5):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90.

1.100 A compound according to Embodiment 1.98 having the formula (6):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90.

1.101 A compound according to Embodiment 1.94 wherein ring A is a 5membered heterocyclic ring containing one nitrogen atom.

1.102 A compound according to Embodiment 1.101 having the formula (7):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90.

1.103 A compound according to embodiment 1.101 wherein moiety.

is selected from groups BAA to BCZ below:

1.104 A compound according to Embodiment 1.101 having the formula (8):

wherein R¹, R² and R⁴ are as defined in any one of Embodiments 1.1 to1.40 and 1.42 to 1.90.

1.105 A compound according to embodiment 1.101 wherein moiety

is selected from groups CAA to CBX below:

1.106 A compound according to embodiment 1.1 wherein Q is a six memberedmonocyclic heterocyclic ring containing 1.2.3 or 4 heteroatom ringmembers selected from N, O and S.

1.107 A compound according to Embodiment 1.106 wherein the moiety:

is selected from groups DAA to DBG below:

1.108 A compound according to embodiment 1.1 wherein Q is a sevenmembered monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatomring members selected from N, O and S.

1.109 A compound according to Embodiment 1.108 wherein the moiety:

is selected from groups EAA to EAB below:

1.110 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1-1 to 1-73, 2-1 to 2-138, 3-1 to 3-16, 4-1 to 4-20 or5-1 to 5-2.

1.111 A compound according to any one of Embodiments 1.1 to 1.110 havinga molecular weight of less than 550.

1.112 A compound according to Embodiment 1.111 having a molecular weightof less than 500.

1.113 A compound according to Embodiment 1.112 having a molecular weightof, or less than 450.

1.114 A compound according to any one of Embodiments 1.1 to 1.113 whichis in the form of a salt.

1.115 A compound according to Embodiment 1.114 wherein the salt is anacid addition salt.

1.116 A compound according to Embodiment 1.115 or Embodiment 1.115wherein the salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment”, in relation to the uses of the compounds of theformula (1), (1a) or (1b), is used to describe any form of interventionwhere a compound is administered to a subject suffering from, or at riskof suffering from, or potentially at risk of suffering from the diseaseor disorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “effective therapeutic amount” as used herein (for example inrelation to methods of treatment of a disease or condition) refers to anamount of the compound which is effective to produce a desiredtherapeutic effect. For example, if the condition is pain, then theeffective therapeutic amount is an amount sufficient to provide adesired level of pain relief. The desired level of pain relief may be,for example, complete removal of the pain or a reduction in the seventyof the pain.

The term “non-aromatic hydrocarbon group” as in “C₁₋₁₀ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group. Thus the term non-aromatic hydrocarbonincludes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkenyl alkyl and so on.

The terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl” aryl, heteroaryland “cycloalkenyl” are used in their conventional sense (e.g. as definedin the IUPAC Gold Book) unless indicated otherwise.

The term “saturated hydrocarbon group” as in “C₁₋₄ saturated hydrocarbongroup” refers to a hydrocarbon group containing no carbon-carbon doublebonds or triple bonds. The saturated hydrocarbon group can therefore bean alkyl group, a cycloalkyl group, a cycloalkylalkyl group, analkylcycloalkyl group or a alkylcycloalkylalkyl group. Examples of C₁₋₄saturated hydrocarbon groups include C₁₋₃ alkyl groups, cyclopropyl,cyclobutyl and cyclopropylmethyl.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

In the definitions of R¹, R², R³ and R⁴ above, where stated, one or twobut not all, carbon atoms of the non-aromatic hydrocarbon group mayoptionally be replaced by a heteroatom selected from O, N and S and (inthe case of R¹ and R⁴) oxidised forms thereof. It will be appreciatedthat when a carbon atom is replaced by a heteroatom, the lower valenciesof the heteroatoms compared to carbon means that fewer atoms will bebonded to the heteroatoms than would have been bonded to the carbon atomthat has been replaced. Thus, for example, replacement of of a carbonatom (valency of four) in a CH₂ group by oxygen (valency of two) willmean that the resulting molecule will contain two less hydrogen atomsand replacement of a carbon atom (valency of four) in a CH₂ group bynitrogen (valency of three) will mean that the resulting molecule willcontain one less hydrogen atom.

Examples of a heteroatom replacements for carbon atoms includereplacement of a carbon atom in a —CH₂CH₂CH₂— chain with oxygen orsulfur to give an ether —CH₂O—CH₂— or thioether —CH₂—S—CH₂—, replacementof a carbon atom in a group CH₂C≡C—H with nitrogen to give a nitrile(cyano) group CH₂C≡N, replacement of a carbon atom in a group—CH₂CH₂CH₂— with C═O to give a ketone —CH₂C(O)—CH₂—, replacement of acarbon atom to a group —CH₂—CH₂—CH₂— with S═O or SO₂ to give a sulfoxide—CH₂—S(O)—CH₂— or sulfone —CH₂—S(O)₂—CH₂—, replacement of a carbon atomin a —CH₂CH₂CH₂— chain with C(O)NH to give an amide —CH₂CH₂C(O)—NH—,replacement of a carbon atom in a —CH₂CH₂CH₂— chain with nitrogen togive an amine —CH₂—NH—CH₂—, and replacement of a carbon atom to a—CH₂CH₂—CH₂— chain with C(O)O to give an ester (or carboxylic add)—CH₂CH₂—C(O)—O—. In each such replacement, at least one carbon atom ofthe hydrocarbon group must remain.

Salts

Many compounds of the formula (1), (1a) or (1b) can exist in the form ofsalts, for example acid addition salts or, in certain cases salts oforganic and inorganic bases such as carboxylate, sulfonate and phosphatesalts. All such salts are within the scope of this invention, andreferences to compounds of the formula (1), (1a) or (1b) include thesalt forms of the compounds as defined in Embodiments 1.114 to 1.116.

The salts are typically add addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described to Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor). ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or add in water or inin organic solvent or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.120) may be formed witha wide variety of acids, both inorganic and organic. Examples of addaddition salts falling within Embodiment 1.120 include mono- or di-saltsformed with an add selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic).L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic adds (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic. (t)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicyclic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric adds, as well as acylated amino adds and cation exchange resins.

Where the compounds of the formula (1), (1a) or (1b) contain an aminefunction, these may form quaternary ammonium salts, for example byreaction with an alkylating agent according to methods well known to theskilled person. Such quaternary ammonium compounds are within the scopeof formula (1), (1a) or (1b).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the add from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

Stereoisomers

Stereoisomers ere isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or ds and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.121), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.116.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.132) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.121which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, AngewChem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric add,(−)-pyroglutamic add, (−)-di-toluoyl-L-tartaric add, (+)-mandelic add,(−)-malic add, aid (−)-camphorsulphonic, separating the diastereoisomersby preferential crystallisation, and then dissociating the salts to givethe individual enantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.133), the inventionprovides compositions containing a compound according to Embodiment1.132 having one or more chiral centres, wherein at least 55% (e.g. atleast 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound ofEmbodiment 1.108 is present as a single optical isomer (e.g. enantiomeror diastereoisomer).

In one general embodiment (Embodiment 1.134), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.132 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.135) the compound ispresent as a single enantiomer.

In another embodiment (Embodiment 1.136), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.137 A compound according to Embodiment 1.132 which is in the form of aracemic mixture of optical isomers.

1.138 A compound according to Embodiment 1.132 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.138 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ¹H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.140), the compound of any one of Embodiments1.1 to 1.138 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment (Embodiment 1.141),however, the compound of any one of Embodiments 1.1 to 1.138 may containone or more radioisotopes. Compounds containing such radioisotopes maybe useful in a diagnostic context.

Solvates

Compounds of the formula (1), (1a) or (1b) as defined in any one ofEmbodiments 1.1 to 1.141 may form solvates. Preferred solvates aresolvates formed by the incorporation into the solid state structure(e.g. crystal structure) of the compounds of the invention of moleculesof a non-toxic pharmaceutically acceptable solvent (referred to below asthe solvating solvent). Examples of such solvents include water,alcohols (such as ethanol, isopropanol and butanol) anddimethylsulphoxide. Solvates could be prepared by recrystallising thecompounds of the invention with a solvent or mixture of solventscontaining the solvating solvent. Whether or not a solvate has beenformed in any given instance can be determined by subjecting crystals ofthe compound to analysis using well known and standard techniques suchas thermogravimetric analysis (TGE), differential scanning calorimetry(DSC) and X-ray crystallography. The solvates can be stoichiometric ornon-stoichiometric solvates. Particularly preferred solvates arehydrates, and examples of hydrates include hemihydrates, monohydratesand dihydrates.

Accordingly, in further embodiments 1.150 and 1.151, the inventionprovides:

1.151 A compound according to any one of Embodiments 1.1 to 1.141 in theform of a solvate.

1.152 A compound according to Embodiment 1.151 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition published by SSCI, Inc of West Lafayette. Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.153), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.141 in an anhydrous form (e.g. anhydrouscrystalline form).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.153 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR)The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD.Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et al. J. Pharm. Sci (1997), 88, 1).

Accordingly, in further embodiments, the invention provides:

1.160 A compound according to any one of Embodiments 1.1 to 1.153 in acrystalline form.

1.161 A compound according to any one of Embodiments 1.1 to 1.153 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.162 A compound according to any one of Embodiments 1.1 to 1.153 whichis in an amorphous form.

Prodrugs

The compounds of the formula (1), (1a) or (1b) as defined in any one ofEmbodiments 1.1 to 1.162 may be presented in the form of a pro-drug. By“prodrugs” is meant for example any compound that is converted in vivointo a biologically active compound of the formula (1), (1a) or (1b), asdefined in any one of Embodiments 1.1 to 1.162.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, UDEPT, etc) Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.170), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.170 wherein the compound contains a functional group which isconvertable under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1), (1a) or (1b) in Embodiments 1.1 to1.170 are complexes (e.g. inclusion complexes or clathrates withcompounds such as cyclodextrins, or complexes with metals) of thecompounds of Embodiments 1.1 to 1.170.

Accordingly, in another embodiment (Embodiment 1.180), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.170 inthe form of a complex or clathrate.

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M1receptor agonists. The muscarinic activity of the compounds can bedetermined using the Phospho-ERK1/2 assay described in Example A below.

A significant advantage of compounds of the invention is that they arehighly selective for the M1 receptor relative to the M2 and M3 receptorsubtypes. Compounds of the invention are not agonists of the M2 and M3receptor subtypes. For example, whereas compounds of the inventiontypically have pEC₅₀ values of at least 6 (preferably at least 6.5) andE_(max) values of greater than 80 (preferably greater than 95) againstthe M1 receptor in the functional assay described in Example A, they mayhave pEC₅₀ values of less than 5 and E_(max) values of less than 20%when tested against the M2 and M3 subtypes in the functional assay ofExample A.

Some compounds of the invention are also highly selective for the M4receptor relative to the M1 receptor. Examples of such compounds includethe compound of Example 1-6, 1-9.1-21 and 2-17.

Other compounds of the invention have activity at both the M1 and M4receptors.

Examples of such compounds include compounds of Examples 1-1 to 1-4 and1-8 to 1-10 and 2-116.

Accordingly, in Embodiments 2.1 to 2.9, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.180 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.180 for useas a muscarinic M1 and/or M4 receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.180 which isa muscarinic M1 receptor agonist having a pEC₅₀ in the range from 6.0 to8.1 and an E_(max) of at least 90 against the M1 receptor in the assayof Example A herein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M1receptor agonist having a pEC₅₀ in the range from 6.5 to 7.5.

2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having anE_(max) of at least 95 against the M1 receptor.

2.6 A compound according to any one of Embodiments 1.1 to 1.180 which isa muscarinic M4 receptor agonist having a pEC₅₀ in the range from 6.0 to9.0 and an E_(max) of at least 90 against the M4 receptor in the assayof Example A herein or an assay substantially similar thereto.

2.7 A compound according to Embodiment 2.6 which is a muscarinic M4receptor agonist having a pEC₅₀ in the range from 6.5 to 9.0.

2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having anE_(max) of at least 95 against the M4 receptor.

2.9 A compound according to any one of Embodiments 2.3 to 2.8 which isselective for the M1 and/or M4 receptor compared to the muscarinic M2and M3 receptors.

2.10 A compound according to Embodiment 2.9 which is selective for theM1 receptor compared to the muscarinic M2 and M3 receptors.

2.11 A compound according to Embodiment 2.9 which is selective for theM4 receptor compared to the muscarinic M2 and M3 receptors.

2.12 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M1 receptor compared to the muscarinic M2, M3 and M4receptors.

2.13 A compound according to any one of Embodiments 2.6 to 2.8 which isselective for the M4 receptor compared to the muscarinic M1, M2 and M3receptors.

2.14 A compound according to any one of Embodiments 2.3 to 2.8 which isselective for the M1 and M4 receptor compared to the muscarinic M2 andM3 receptors.

2.15 A compound according to any one of Embodiments 2.3 to 2.14 whichhas a pEC₅₀ of less than 5 and an E_(max) of less than 50 against themuscarinic M2 and M3 receptor subtypes.

2.16 A compound according to Embodiment 2.15 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M2 andM3 receptor subtypes.

2.17 A compound according to any one of Embodiments 1.1 to 1.180 andEmbodiments 2.3 to 2.16 for use in the treatment of a disease orcondition mediated by the muscarinic M1 receptor.

By virtue of their muscarinic M1 and/or M4 receptor agonist activity,compounds of the inventor can be used in the treatment of Alzheimer'sdisease, schizophrenia and other psychotic disorders, cognitivedisorders and other diseases mediated by the muscarinic M1 and/or M4receptor, and can also be used in the treatment of various types ofpain.

Accordingly, in Embodiments 2.18 to 2.34, the invention provides:

2.18 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of a cognitive disorder or psychotic disorder.

2.19 A compound for use in according to Embodiment 2.18 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, MildCognitive Impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions inducingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as Multiinfarctdementia, alcoholic dementia, hypotiroidism-related dementia, anddementia associated to other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced statesneurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine. Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders,epilepsy and schizo-affective disorder.

2.20 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of Alzheimer's disease.

2.21 A compound according to any one of Embodiments 1.1 to 1.180 for usein the treatment of Schizophrenia.

2.22 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.180.

2.23 A method according to Embodiment 2.20 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.19.

2.24 A method according to Embodiment 2.23 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.25 A method according to Embodiment 2.24 wherein the cognitivedisorder is Schizophrenia.

2.26 The use of a compound according to any one of Embodiments 1.1 to1.180 for the manufacture of a medicament for the treatment of acognitive disorder.

2.27 The use according to Embodiment 2.26 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.11.

2.28 The use according to Embodiment 2.27 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.29 The use according to Embodiment 2.29 wherein the cognitive disorderis Schizophrenia.

2.30 A compound according to any one of Embodiments 1.1 to 1.180 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

2.31 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.180.

2.32 A compound according to any one of Embodiments 1.1 to 1180 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.33 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in Glaucoma and treatment of dry eyes and drymouth inducing Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.180.

2.34 The use of a compound according to any one of Embodiments 1.1 to1.180 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, duster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in Glaucoma and treatment of dry eyes and dry mouth inducingSjogren's Syndrome.

2.35 The use of a compound according to any one of Embodiments 1.1 to1.180 for the treatment of addition.

2.36 The use of a compound according to any one of Embodiments 1.1 to1.180 for the treatment of movement disorders such as Parkinson'sdisease, ADHD, Huntingdon s disease, tourette s syndrome and othersyndromes associated with dopaminergic dysfunction as an underlyingpathogenetic factor driving disease.

Methods for the Preparation of Compounds of the Formula (1), (1a), or(1b)

Compounds of the formula (1), (1a) or (1b) can be prepared in accordancewith synthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.180, which process comprises:

(A) the reaction of a compound of the formula (10)

with a compound of the formula (11):

under reductive amination conditions, wherein R′, R², R³, R⁴ and Q areas defined m any one of Embodiments 1.1 to 1.180; or

(B) the reaction of a compound of the formula (12)

with a compound of the formula Cl—C(═O)—CH₂R⁴, in the presence of abase; or

(C) the reaction of a compound of the formula (10)

with a compound of the formula (13):

under nucleophilic substitution conditions; wherein R¹, R², R³, R⁴ and Qare as defined in any one of Embodiments 1.1 to 1.180; and optionally:

(D) converting one compound of the formula (1), (1a) or (1b) to anothercompound of the formula (1), (1a) or (1b).

In process variant (A), the piperidine heterocycle (10) is reacted withthe substituted ketone (11) under reductive amination conditions. Thereductive amination reaction is typically carried out at ambienttemperature using a borohydride reducing agent such as sodiumtriacetoxy-borohydride in a solvent such as dichloromethane ordichloroethane containing acetic acid.

In process variant (C), the piperidine heterocycle (10) is reacted withthe sulfonic ester (13, R=methyl, trifluoromethyl or 4-methyl phenyl) ina nucleophilic substitution reaction which is typically carried out withmild heating (e.g. to a temperature of from about 40° C. to about 70°C.) either neat with no solvent, or in a suitable solvent such astetrahydrofuran, acetonitrile or dimethylacetamide.

Intermediate compounds of the formula (12) can be prepared by the seriesof reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine heterocycle (10) is reacted withthe Boc-protected spiroketone (14) under reductive amination conditions.The reductive amination reaction is typically carried out with mildheating (e.g. to a temperature of from about 40° C. to about 70° C.) inthe presence of either sodium cyanoborohydride in combination with zincchloride or sodium triacetoxyborohydride in combination with titaniumisopropoxide in a solvent such as dichloromethane or dichloroethanecontaining acetic acid to give an intermediate piperidine compound (15)which is then deprotected by removal of the Boc group by treatment withacid (e.g. trifluoroacetic add in dichloromethane) to give the compound(12).

Compounds of the formula (12) can also be prepared by the sequence ofreactions shown in Scheme 2 below.

In Scheme 2, the Boc-protected spiroketone (14) is reduced to thealcohol (16) using sodium borohydride in methanol. The alcohol (16) isthen activated as the sulfonic ester (17, R=methyl, trifluoromethyl or4-methylphenyl) using the corresponding sulfonyl chloride indichloromethane in the presence of a tertiary amine such astriethylamine or N,N-diisopropylethylamine. The sulfonic ester (17) isreacted with the piperidine heterocycle (10) in a nucleophilicsubstitution reaction which is typically carried out with mild heating(e.g. to a temperature of from about 40° C. to about 70° C.) eitherneat, with no solvent, or in a suitable solvent such as tetrahydrofuran,acetonitrile or dimethylacetamide to give compound (15) which is thendeprotected by removal of the Boc group by treatment with acid (e.g.trifluoroacetic acid in dichloromethane) to give the compound (12).

Once formed, one compound of the formula (1), (1a) or (1b), or aprotected derivative hereof, can be converted into another compound ofthe formula (1), (1a) or (1b) by methods well known to the skilledperson Examples of synthetic procedures for converting one functionalgroup into another functional group are set out in standard texts suchas Advanced Organic Chemistry and Organic Syntheses (see referencesabove) or Fiesers' Reagents for Organic Synthesis, Volumes 1-17, JohnWiley, edited by Mary Fieser (ISBN: 0-471-58283-2). Examples of thesetransformations include amide bond formation, urea formation, carbamateformation, alkylation reactions, N-arylation reaction and C—C bondcoupling reactions.

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1), (1a) or (1b) as defined in any one ofEmbodiments 1.1 to 1.180 together with at least one pharmaceuticallyacceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1),(1a) or (1b) can be formulated in accordance with known techniques, seefor example. Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrates (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcelluose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1), (1a) or (1b) will generally bepresented in unit dosage form and, as such, will typically containsufficient compound to provide a desired level of biological activity.For example, a formulation may contain from 1 nanogram to 2 grams ofactive ingredient, e.g. from 1 nanogram to 2 milligrams of activeingredient. Within these ranges, particular sub-ranges of compound are0.1 milligrams to 2 grams of active ingredient (more usually from 10milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1microgram to 20 milligrams (for example 1 microgram to 10 milligrams,e.g. 0.1 milligrams to 2 milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1-1 to 5-2

The compounds of Examples 1-1 to 5-2 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 3.

TABLE 1

Example 1-1

Example 1-2

Example 1-3

Example 1-4

Example 1-5

Example 1-6

Example 1-7

Example 1-8

Example 1-9

Example 1-10

Example 1-11

Example 1-12

Example 1-13

Example 1-14

Example 1-15

Example 1-16

Example 1-17

Example 1-18

Example 1-19

Example 1-20

Example 1-21

Example 1-22

Example 1-23

Example 1-24

Example 1-25

Example 1-26

Example-1-27

Example 1-28

Example 1-29

Example 1-30

Example 1-31

Example 1-32

Example 1-33

Example 1-34

Example 1-35

Example 1-36

Example 1-37

Example 1-38

Example 1-39

Example 1-40

Example 1-41

Example 1-42

Example 1-43

Example 1-44

Example 1-45

Example 1-46

Example 1-47

Example 1-48

Example 1-49

Example 1-50

Example 1-51

Example 1-52

Example 1-53

Example 1-54

Example 1-55

Example 1-56

Example 1-57

Example 1-58

Example 1-59

Example 1-60

Example 1-61

Example 1-62

Example 1-63

Example 1-64

Example 1-65

Example 1-66

Example 1-67

Example 1-68

Example 1-69

Example 1-70

Example 1-71

Example 1-72

Example 1-73

Example 2-1

Example 2-2

Example 2-3

Example 2-4

Example 2-5

Example 2-6

Example 2-7

Example 2-8

Example 2-9

Example 2-10

Example 2-11

Example 2-12

Example 2-13

Example 2-14

Example 2-15

Example 2-16

Example 2-17

Example 2-18

Example 2-19

Example 2-20

Example 2-21

Example 2-22

Example 2-23

Example 2-24

Example 2-25

Example 2-26

Example 2-27

Example 2-28

Example 2-29

Example 2-30

Example 2-31

Example 2-32

Example 2-33

Example 2-34

Example 2-35

Example 2-36

Example 2-37

Example 2-38

Example 2-39

Example 2-40

Example 2-41

Example 2-42

Example 2-43

Example 2-44

Example 2-45

Example 2-46

Example 2-47

Example 2-48

Example 2-49

Example 2-50

Example 2-51

Example 2-52

Example 2-53

Example 2-54

Example 2-55

Example 2-56

Example 2-57

Example 2-58

Example 2-59

Example 2-60

Example 2-61

Example 2-62

Example 2-63

Example 2-64

Example 2-65

Example 2-66

Example 2-67

Example 2-68

Example 2-69

Example 2-70

Example 2-71

Example 2-72

Example 2-73

Example 2-74

Example 2-75

Example 2-76

Example 2-77

Example 2-78

Example 2-79

Example 2-80

Example 2-81

Example 2-82

Example 2-83

Example 2-84

Example 2-85

Example 2-86

Example 2-87

Example 2-88

Example 2-89

Example 2-90

Example 2-91

Example 2-92

Example 2-93

Example 2-94

Example 2-95

Example 2-96

Example 2-97

Example 2-98

Example 2-99

Example 2-100

Example 2-101

Example 2-102

Example 2-103

Example 2-104

Example 2-105

Example 2-106

Example 2-107

Example 2-108

Example 2-109

Example 2-110

Example 2-111

Example 2-112

Example 2-113

Example 2-114

Example 2-115

Example 2-116

Example 2-117

Example 2-118

Example 2-119

Example 2-120

Example 2-121

Example 2-122

Example 2-123

Example 2-124

Example 2-125

Example 2-128

Example 2-127

Example 2-128

Example 2-129

Example 2-130

Example 2-131

Example 2-132

Example 2-133

Example 2-134

Example 2-135

Example 2-136

Example 2-137

Example 2-138

Example 3-1

Example 3-2

Example 3-3

Example 3-4

Example 3-5

Example 3-6

Example 3-7

Example 3-8

Example 3-9

Example 3-10

Example 3-11

Example 3-12

Example 3-13

Example 3-14

Example 3-15

Example 3-16

Example 4-1

Example 4-2

Example 4-3

Example 4-4

Example 4-5

Example 4-6

Example 4-7

Example 4-8

Example 4-9

Example 4-10

Example 4-11

Example 4-12

Example 4-13

Example 4-14

Example 4-15

Example 4-16

Example 4-17

Example 4-18

Example 4-19

Example 4-20

Example 5-1

Example 5-2

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Broker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ:)=values. The following abbreviations are usedfor the multiplicity of the NMR signals: s=singlet, br=broad d=doublet,t=triplet, q=quartet, quint=qujntet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 80-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions TLCfor monitoring reactions refers to TLC run using the specified mobilephase and Silica gel F254 (Merck) as a stationary phase.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions:

LCMS Methods A and B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micro massZQ; Column Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; Gradient [time (min)/solvent D in C(%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 orMethod B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents:solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL ammonia solution); Injection volume 3 μL; UV detection 230 to400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method C

Instruments: Agilent 1260 Infinity LC with Diode Array Detector, Agilent6120B Single Quadrupole MS with API-ES Source; Column: PhenomenexGemini-NX C-18.3 micron, 2.0×30 mm; Gradient [time (min)/solvent B in A(%)]: Method: 0.00/5, 2.00/95, 2.50/95, 2.60/5, 3.00/5; Solvents:solvent A=2.5 L H₂O+2.5 mL of (28% NH3 In H₂O), solvent B=2.5 L MeCN+129mL H₂O+2.7 mL of (28% NH3 In H₂O); Injection volume 0.5 μL; UV detection190 to 400 nM; column temperature 40° C.; Flow rate 1.5 mL/min.

LCMS Methods P and E

Instruments: HP 1100 with G1315A DAD, Micromass ZQ; Column: WritersX-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3micron, 2.0×30 mm; Gradient [time (min)/solvent D in C (%)]: Method D:0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or Method E: 0.00/2,0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; Solvents: solvent C=2.5 LH₂O+2.5 mL 28% ammonia in H₂O solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL 28% ammonia in H₂O solution); Injection volume 1 μL; UVdetection 230 to 400 nM; Mass detection 130 to 800 AMU (+ve and −veelectrospray); column temperature 45° C.; Flow rate 1.5 mL/min.

LCMS Method F:

Instruments: Waters Acquity H Class, Photo Diode Array, SQ Detector;Column: BEH C18, 1.7 micron, 2.1×50 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/5, 0.40/5, 0.8/35, 1.20/55, 2.50/100, 3.30/100 4.00/5;Solvents: solvent A=5 mM ammonium acetate and 0.1% formic acid in H₂O;solvent B=0.1% formic add in MeCN; Injection volume 2 μL; UV detection200 to 400 nM. Mass detection 100 to 1200 AMU (+ve electrospray); columnat ambient temperature; Flow rate 0.5 mL/min.

LCMS Method G:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector Column:X-Bridge C18, 5 micron, 150×4 6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10 12.00/10;Solvents: solvent A=0.1% ammonia in H₂O, solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method H:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector. Column:X-Bridge C18, 5 micron, 150×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.00/100, 7.00/50, 9.00/0, 11.00/0, 11.01/100, 12.00/100;Solvents: solvent A=0.1% ammonia in H₂O; solvent B=0.1% ammonia in MeCN;Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method I:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 150×4.6 mm; Gradient [time (min)/solvent B inA (%)]: 0.00/5, 5.00/90, 5.80/95, 10/95; Solvents solvent A=0.1% ammoniain H₂O; solvent B=0.1% ammonia in MeCN; Injection volume 10 μL; UVdetection 200 to 400 nM; Mass detection 60 to 1000 AMU (+veelectrospray); column at ambient temperature; Flow rate 1.0 mL/min.

LCMS Method J:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 5 micron, 150×4 6 mm, Gradient [time (min)/solvent B in A(%)]: 0.01/10, 5.00/90, 7.00/100, 11.00/100, 11.01/10, 12.00/10;Solvents: solvent A=20 mM ammonium acetate in H₂O; solvent B=MeOH;Injection volume 10 μL, UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method K:

Instruments: Waters 2695, Photo Diode Array, ZQ-2000 Detector; Column:X-Bridge C18, 3.5 micron, 50×4.6 mm; Gradient [time (min)/solvent B in A(%)]: 0.01/0, 0.20/0, 5.00/90, 5.80/95, 7.20/95, 7.21/100, 10.00/100;Solvents solvent A=0.1% ammonia in H₂O; solvent B=01% ammonia in MeCN:Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to1000 AMU (+ve electrospray); column at ambient temperature; Flow rate1.0 mL/min.

LCMS Method L

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity BEH C-18, 1.7 micron. 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/2, 2.00/2, 7.00/50, 6.50/80, 9.50/2, 10.0/2; Solvents:solvent A=5 mM ammonium acetate in water, solvent B=acetonitrile;Injection volume 1 μL; Detection wavelength 214 nm; Column temperature30° C., Flow rate 0.3 mL per min.

LCMS Method M

Instruments: Agilent 1260 Infinity series UHPLC; ELSD: Agilent 1260Infinity; Column: Acquity C-18, 1.7 micron, 2.1×50 mm; Gradient [time(min)/solvent B in A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90,8.00/90, 9.00/10, 10.00/10; Solvents: A=5 mM ammonium acetate in water,B=acetonitrile; Injection volume: 1 μL; Detection by ELSD; Columntemperature: 40° C.; Flow rate: 0.6 mL per/min.

LCMS Method N

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity BEH C-18, 1.7 micron, 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/2, 0.50/2, 1.50/20, 4.00/92, 5.00/92, 5.50/50, 6.00/2;Solvents: solvent A=5 mM ammonium acetate in water; solventB=acetonitrile; Injection volume 1 μL; Detection wavelength 214 nm;Column temperature 35° C.; Flow rate 0.6 mL per min.

LCMS Method O

Instruments: Waters Acquity UPLC, Waters 3100 PDA Detector, SQD; Column:Acquity HSS-T3, 1.8 micron, 2.1×100 mm; Gradient [time (min)/solvent Bin A (%)]: 0.00/10, 1.00/10, 2.00/15, 4.50/55, 6.00/90, 8.00/90,9.00/10, 10.00/10; Solvents: solvent A=0.1% trifluoroacetic acid inwater; solvent B=acetonitrile; injection volume 1 μL; Detectionwavelength 214 nm; Column temperature 30° C.; Row rate 0.3 mL per min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, UV activity.

Abbreviations

-   AcOH=acetic acid-   CDI=1,1′-Carbonyldiimidazole-   d=day(s)-   DAST=diethylaminosulfur trifluoride-   DCE=dichloroethane-   DCM=dichloromethane-   DIPEA=disopropylethylamine-   DIAD=d isopropyl azodicarboxylate-   DMF=dimethylformamide-   DMP=Dess-Martin periodinane-   DMSO=dimethylsulfoxide-   ES=electro spray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   HATU=1-[Bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   LiAlH₄/LAH=Lithium aluminium hydride-   MeCN=acetonitrile-   MeOH=methanol-   min=minute(s)-   MS=mass spectrometry-   Et₃N=triethylamine-   NMR=nuclear magnetic resonance-   rt=room temperature-   sat=saturated-   sol.=solution-   STAB=sodium triacetoxyborohydride-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

Synthesis of Intermediates Procedure for the Preparation of Intermediate2, Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate

6-Boc-2-oxo-6-azaspiro[3.4]octane (3.37 g, 15 mmol) was addedportionwise to hydrogen chloride (4 M dioxane solution, 50 mL, 210mmol). Caution: effervescence After 24 h, the reaction was concentratedin vacuo and the residual solid was dissolved in a mixture of Et₃N (418ml, 30 mmol) and DCM (86 mL) On completion of dissolution, the solutionwas immediately cooled to 0° C., then ethyl chloroformate (1.57 mL, 18.5mmol) was added dropwise. After 18 h, the mixture was poured intodichloromethane (100 mL) and NaHCO₃ (aq) (100 mL) and extracted (2×100mL). The organic layers were collected, washed with brine (20 mL), driedover MgSO₄, then the residue after evaporation was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 100 g,40-63 μm, 80 Å, 50 mL per min, gradient 0% to 4% MeOH in DCM]) to giveIntermediate 2, ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate as acolourless oil (2.47 g, 83%). The data for the title compound are inTable 2.

Procedure for the Preparation of Intermediate 3, methyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate

6-Boc-2-oxo-6-azaspiro[3.4]octane (5.00 g, 22.2 mmol) was addedportionwise to hydrogen chloride (4 M dioxane solution, 45 mL, 180 mmol)In dichloromethane (5 mL). Caution: effervescence. After 2 h, thereaction was concentrated in vacuo and 1.29 g of the residual soliddissolved in a mixture of triethylamine (2.23 ml, 16.0 mmol) anddichloromethane (10 mL). On completion of dissolution, the solution wasimmediately cooled to 0° C., then methyl chloroformate (0.68 mL, 8.83mmol) was added dropwise. After 3 h, the mixture was poured intodichloromethane (50 mL), washed with NaHCO₃ (aq) (2×50 mL) and extractedwith DCM (50 mL). The organic layers were combined, washed with brine(50 mL), passed through a Biotage Phase Separator, the solvent wasremoved in vacuo and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 40mL per min, gradient 0% to 10% MeOH in DCM]) to give Intermediate 3,methyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate as an orange oil (0.93g, 66%). The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 4,2-fluoroethyl2-oxo-6-azaspiro[3.4]octane-8-carboxylate

tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (5 g, 22.19 mmol)was stirred in HCl in 1,4-dioxane (25 mL) solution for 10 h at rt. Thereaction mixture was was concentrated in vacuo and triturated withacetone (3×50 mL) to give 6-azaspiro[3.4]octan-2-one (2.77 g, 55.4%) asa brown gum. The residue was dissolved in dry DCM (20 mL) and Et*N (0.7mL, 4.8 mmol) was added. The reaction mixture was cooled to 0° C. and2-fluoroethyl carbonochloridate (0.45 g, 3.6 mmol) was added. Thereaction mixture to stir at 30° C. for 5 h then diluted with water (50mL), extracted with DCM (2×100 mL), organic layers were combined, dried(Na₂SO₄), and the solvent was removed in vacuo. The residue was purifiedby column chromatography (normal phase, 60-120 mesh silica, 0 to 10%EtOAc in Hexane) to give Intermediate 4,2-fluoroethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.2 g, 38.8%) as a brown gum.The data for the the compound are in Table 2.

Procedure for the Preparation of Intermediates 20 and 21,4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidine trifluoroacetate and4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidine trifluoroacetateRespectively

4-(1-Methylimidazol-2-yl)piperidine hydrochloride (1 g, 4.96 mmol) wassuspended in a mixture of anhydrous DCM (20 mL) and Et₃N (2.1 mL, 15.1mmol) and cooled in an ice-water bath. (BOC)₂O (1.19 g, 5.45 mmol) wasadded portion wise over 5 mins, the mixture was warmed to rt and stirredfor 48 h. The mixture was diluted with DCM, washed with saturatedaqueous NaHCO₃ (×2) and brine (×1), then passed through a phaseseparator and concentrated in vacuo to give tert-butyl4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.34 g, quant.)as a solid.

LCMS (Method C): m/z 266 (M+H)⁺ (ES⁺), at 1.43 min, UV active.

tert-Butyl 4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (0.250g, 0.942 mmol) was dissolved in MeCN (7.5 mL), treated with NCS (0.314g, 2.35 mmol) and stirred at rt overnight. The reaction mixture wasconcentrated onto flash silica (15 mL) in vacuo. The resulting powderwas purified by column chromatography (normal phase, [Biotage SNAPcartridge KP-sil 50 g, 40-63 μm, 60 Å, 40 mL per min, grad ent 2% to 10%Solvent A in DCM over 15 column volumes, where solvent A is 10% of (7 MNH₃/MeOH) in MeOH]) to give a mixture containing tert-butyl4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate andtert-butyl4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate andsuccinimide (0.495 g).

LCMS (Method C): monochloro: m/z 300/332 (M+H)⁺ (ES⁺), at 1.68 min, UVactive; dichloro: m/z 334/336/338 (M+H)⁺ (ES⁺), at 1.67 min UV active.Ratio of monochloro; dichloro ˜16:1 by LC-UV.

The mixture containing tert-butyl4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate andtert-butyl4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate andsuccinimide (0.495 g) was dissolved in DCM (5 mL), treated with TFA (5mL) and stirred at rt for 6 h. The reaction mixture was concentrated invacuo and the residue azeotroped with toluene (×2) to afford a crudemixture of Intermediate 20,4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidine trifluoroacetate andIntermediate 21, 4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidinetrifluoroacetate mixed with succinimide. Assumed quantitative yield.Used with no further purification. The data for the title compounds arein Table 2.

Procedure for the Preparation of Intermediates 22 and 25,4-(5-chloro-1H-imidazol-2-yl)piperidine dihydrobromide and4-(4,5-dichloro-1H-imidazol-2-yl)piperidine Dihydrobromide Respectively

Ethyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.40 g, 1.79 mmol)was dissolved in MeCN (12 mL), treated with NCS (0.360 g, 2.70 mmol) andstirred at rt for 5.5 h. The reaction mixture was concentrated ontoflash silica (˜10 mL) in vacuo. The resulting powder was purified bycolumn chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50g, 40-63 μm, 60 Å, 40 mL per min, gradient 0% to 5% Solvent A in DCMover 15 column volumes, then 5% Solvent A in DCM over 5 column volumes,where solvent A is 10% of (7 M NH₃/MeOH) in MeOH]) to give the separatedethyl 4-(5-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate and ethyl4-(4,5-dichloro-1M-imidazol-2-yl)piperidine-1-carboxylate, both mixedwith succinimide. Each was dissolved in DCM, washed with H₂O (×3),passed through a phase separator and concentrated in vacuo to removesuccinimide.

Ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate (0.12 g,26%), LCMS (Method C): m/z 258/260 (M+H)⁺ (ES⁺), at 1.34 min, UV active.

Ethyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate (0.24 g,45%), LCMS (Method C): m/z 292/294/296 (M+H)⁺ (ES⁺), at 1.24 min, UVactive.

Ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate (0.12 g,0.47 mmol) was dissolved in AcOH (2 mL), treated with 48% aqueous HBr (2mL) and heated at reflux at 120° for 2 h. The reaction mixture wasconcentrated in vacuo, the residue was azeotroped with toluene (×1) andconcentrated in vacuo to afford a sold Assumed to be Intermediate 22,4-(5-chloro-1H-imidazol-2-yl)piperidine dihydrobromide salt inquantitative yield. Used immediately.

Ethyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate (0.24 g,0.82 mmol) was dissolved in AcOH (2 mL), treated with 48% aqueous HBr (2mL) and heated ˜120° C. for 2 h. The reaction mixture was concentratedin vacuo, the residue was azeotroped with toluene (×1) and concentratedin vacuo to afford a sold. Assumed to be Intermediate 26,4-(4,5-Dichloro-1H-imidazol-2-yl)piperidine dihydrobromide inquantitative yield. Used immediately. The data for the title compoundsare in Table 2.

Procedure for the Preparation of Intermediate 46, tert-butyl4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate andIntermediate 33, 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]piperidine

tert-Butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.4 mmol) wasdissolved in MeOH (10 mL) and followed by addition of 7M methanolicammonia cooled at 0° C. for 30 mins followed by portion wise addition of3,3-dibromo-1,1,1-trifluoropropan-2-one (5.07 g, 18.5 mmol) Theresulting reaction mixture was stirred at 25° C. for 2 h, solvents wereremoved in vacuo and the residue was partitioned between H₂O (80 mL) andEtOAc (50 mL), the aqueous layer was extracted with EtOAc (2*50 mL),organic layers were combined, dried (Na₂SO₄), solvent was removed invacuo and residue was purified by column chromatography (Activated basicAlumina at 0.5% MeOH in DCM) to give Intermediate 46, tert-butyl4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.80g, 60%) as a white sold. The data for the subtitle compound are in Table2.

tert-Butyl4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1 g,3.13 mmol) was dissolved in 1,4-dioxane (5 mL) and followed by dropwiseaddition of HCl in 1,4-dioxane (20 mL, 3M solu.). The resulting reactionmixture was stirred at 30° ° C. for 16 h, the solvents were removed invacuo and the residue was purified by triturating with diethyl ether(3×5 mL) to give Intermediate 33,4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine hydrochloride (650mg, 95%) as a white solid. The data for the title compound are in Table2.

Procedure for the Preparation of Intermediate 37,4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]piperidineHydrochloride Salt

tert-Butyl4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (200mg, 0.63 mmol) was dissolved in THF (5 mL) and 60% sodium hydride (74mg, 1.88 mmol) added at 0° C. The reaction mixture was stirred at 0° C.for 10 mins, then methyl iodide (0.06 mL, 0.96 mmol) was added and theresulting reaction mixture was stirred at 25° C. for 2 h. The reactionmixture was partioned between H₂O (60 mL) and EtOAc (45 mL), the aqueouslayer was further extracted with EtOAc (2×45 mL), the organic layerswere combined, dried (Na₂O₄) and the solvents were removed in vacuo. Theresidue was purified by column chromatography (Normal silica, mesh size:60-120, 0% to 2.0% to 3.5% MeOH in DCM) to give tert-butyl4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(190 mg, 91%) as a yellow gum.

LCMS (Method F): m/z 334 (M+H)⁺ (ES⁺), at 2.31 min, UV active

tert-Butyl4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(200 mg, 0.6 mmol) was dissolved in 1,4-dioxane (5 mL) and followed bydropwise addition of HCl in 1,4-dioxane (20 mL, 4M solu.). The resultingreaction mixture was stirred at 30° ° C. for 16 h. the solvents wereremoved in vacuo and the residue was purified by triturating withdiethyl ether (3×5 mL) to give Intermediate 37,4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]piperidinehydrochloride salt (140 mg, 86.8%) as a white solid. The data for thetitle compound are in Table 2

Procedure for the Preparation of Intermediate 43,4-(1,3,4-oxadiazol-2-yl)piperidine

Ethyl piperidine-4-carboxylate (3.0 g, 19.1 mmol) was dissolved in THF(15 mL) and Cs₂CO₃ (7.4 g, 22.9 mmol) added at 0° C. The resultingreaction mixture was stirred at 0-5° C. for 10 mins, then benzylchloroformate (3.2 g, 19.1 mmol) was added dropwise, and the reactionmixture was stirred at room temperature for 18 h. The reaction mixturewas partitioned between H₂O (100 mL) and EtOAc (200 mL), the aqueouslayer was extracted with EtOAc (2×200 mL), the organic layers werecombined, dried (Na₂SO₄) and the solvent was removed in vacuo. Theresidue was purified by column chromatography (Normal silica, mesh size:60-120.0% to 10% EtOAc in Hexane) to give 1-benzyl 4-ethylpiperidine-1,4-dicarboxylate (4.2 g, 76.4%) as a yellow solid.

LCMS (Method F): m/z 292 (M+H)⁺ (ES⁺), at 2.35 min, UV active

1-Benzyl 4-ethyl piperidine-1,4-dicarboxylate (4.2 g, 14.43 mmol) wasdissolved in EtOH (10 mL), hydrazine monohydrate (10 mL, 5.41 mmol) wasadded and the resulting reaction mixture was stirred at 90° C.overnight. The solvents were removed in vacuo and the crude product wastriturated with pentane and hexane to give benzyl4-(hydrazinylcarbonyl)piperidine-1-carboxylate (3.8 g, 95%) as a whitesolid.

LCMS (Method H): m/z 278 (M+H)⁺ (ES⁺), at 1.78 min, UV active

Benzyl 4-(hydrazinylcarbonyl)piperidine-1-carboxylate (0.5 g, 1.79mmol), was dissolved in triethylorthoformate (8 mL) and then TFA (0.1mL) was added. The resulting reaction mixture was stirred at 80° C.overnight. The reaction mixture was partitioned between H₂O (50 mL) andEtOAc (100 mL), the aqueous layer was extracted with EtOAc (2×100 mL),the organic layers were combined, dried (Na₂SO₄) and the solvent wasremoved in vacuo. The residue was purified by column chromatography(Normal silica, mesh size: 60-120, 50% to 80% EtOAc in Hexane) to givebenzyl 4-(1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (0.19 g, 38%) asa yellow solid.

LCMS (Method H): m/z 288 (M+H)⁺ (ES⁺), at 2.03 min, UV active

Benzyl 4-(1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (0.15 g, 0.52mmol) was dissolved in MeOH (10 mL). Dry 10% Pd on carbon catalyst (20mg) was added and the reaction mixture was purged with H₂ gas at roomtemperature. The reaction mixture was stirred at room temperature for 12h under the H₂ atmosphere. The reaction mass was filtered through Celiteand the was solvent removed in vacuo to give Intermediate 43,4-(1,3,4-oxadiazol-2-yl)piperidine (0.078 g, 99%) as a colorless gum.The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 44,4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine

Acetonitrile (40.0 mL) and 50% hydroxylamine in water (4.20 mL) wereheated at reflux at 90° C. for 24 h. The reaction mixture was cooled to0° C. and filtered. The residue was dried to give(Z)—N-hydroxyethanimidamide (2.1 g, >100%) as a white crystalline solid.

LCMS (Method H): m/z 74 (M+H)⁺ (ES⁺), at 1.86 min, UV inactive

(Z)—N-hydroxyethanimidamide (0.50 g, 6.75 mmol) and methylpiperidine-4-carboxylate (1.17 g, 7.42 mmol) were dissolved in ethanol(20 mL). 21% Sodium ethoxide solution in ethanol (0.92 mL, 13.4 mmol)was added dropwise and the reaction mixture was stirred for 30 min at rtand then at 100° C. for 16 h. The solvents were removed in vacuo and theresidue was purified by column chromatography (normal-Phase Silica, 0 to12% methanol in DCM) to give Intermediate 44,4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine (380 mg, 34%) as a yellowgum. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 47,4-(1H-imidazol-2-yl)piperidin-4-ol Hydrochloride

1H-imidazole (8.0 g, 117.5 mmol) was dissolved in DMF (100 mL), sodiumhydride (4.7 g, 117.5 mmol, 60% in oil) was added at room temperature.The reaction mixture was stirred at rt for 2 h. 2-(trimethylsilyl)ethoxymethyl chloride (20.5 g, 123.38 mmol) was added dropwise to thereaction mixture at rt, after addition the reaction mixture was stirredat rt for 16 h Reaction mixture was poured onto ice cold water (1×0 mL)and extracted with EtOAc (500 mL), the aqueous layer was furtherextracted with EtOAc (2×500 mL), organic layers were combined, dried(Na₂SO₄) and the solvent were removed in vacuo. The residue was purifiedby column chromatography (normal phase silica, 0 to 1% methanol in DCM)to give 1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazole (16.2 g,68.6%) as light green gum.

LCMS (Method F): m/z 109 (M+H)⁺ (ES⁺), at 1.73 min, UV active

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5.0 g, 25.0 mmol) wasdissolved in THF (50 mL) and cooled to −78° C. n-BuLi (19.0 mL, 30 mmol,1.6M in hexane) was added dropwise at −78° C., the reaction mixture wasthen stirred at −78° C. for 1 h. A solution of tert-butyl4-oxopiperidine-1-carboxylate (5.53 g, 27 mmol) in THF (10 mL) was addeddropwise at −78° C. to the reaction mixture. The reaction mixture wasallowed to warm to rt over 2 h. The reaction mixture was quenched withsaturated NH₄Cl solution (100 mL), extracted with EtOAc (50 mL), aqueouslayer was further extracted with EtOAc (2×50 mL), the organic layerswere combined, dried (Na₂SO₄), and the solvents were removed in vacuo.The residue was purified by column chromatography (normal phase silica,0 to 20% EtOAc in hexane) to give tert-butyl4-hydroxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(5 g, 80.0%) as light yellow gum.

LCMS (Method F): m/z 398 (M+H)⁺ (ES⁺), at 2.16 min, UV active

tert-Butyl4-hydroxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(2.0 g, 5.0 mmol) was dissolved in 4M HCl in 1,4-Dioxane (20 mL), thereaction mixture was stirred at rt for 10 h. The solvents were removedin vacuo, and the residue was triturated with acetone (3×20 mL) to giveIntermediate 47, 4-(1H-imidazol-2-yl)piperidin-4-ol (0.5 g, 60.2%) asbrown gum. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 48,4-(1H-imidazol-2-yl)-4-methoxypiperidine Hydrochloride Salt

tert-Butyl4-hydroxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(2.0 g, 5.0 mmol) was dissolved in DMF (20 mL). The solution was cooledto 0° C. under Na and NaH (0.24 g, 10.0 mmol) was added. The reactionmixture was stirred at 0° C. for 30 min then methyl iodide (1.07 g, 7.5mmol) was added and the reaction mixture was stirred at n for 2 h. Thereaction mixture partitioned between water (50 mL) and EtOAc (50 mL),the aqueous layer was further extracted with EtOAc (3×100 mL), theorganic layers were combined, dried (Na₂SO₄), and the solvents wereremoved in vacuo. The residue was purified by column chromatography(normal phase, 60-120 mesh silica, 0 to 10% EtOAc in Hexane) to givetert-butyl4-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(1.5 g, 75.0%) as yellow gum.

tert-butyl4-methoxy-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(15 g, 3.6 mmol) was dissolved in 4M HCl in 1,4-Dioxane (20 mL), thereaction mixture was stirred at rt for 10 h. The solvents were removedin vacuo, and the residue was triturated with acetone (3×20 mL) to giveIntermediate 48, 4-(1H-imidazol-2-yl)-4-methoxypiperidine (0.5 g, 76.0%)as brown solid. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 49,4-(1-methyl-1H-imidazol-2-yl)piperidin-4-ol Hydrochloride Salt

1-Methyl imidazole (6.0 g, 73.0 mmol) was dissolved in THF (100 mL) atrt and the reaction mixture was cooled to −78° C. under nitrogen, n-BuLiin hexane (45.4 mL 73.0 mmol) was slowly added. The reaction mixture wasgradually warmed to 40° C. and stirred for 4 h. then cooled to −78° C.tert-Butyl 4-oxopiperidine-1-carboxylate (14.56 g, 73.0 mmol) in THF(100 mL) was added. The reaction mixture was gradually warmed to 40° C.and stirred for 10 h, then quenched with water (50 mL). The reactionmixture was partitioned between EtOAc (200 mL) and water (150 mL), theaqueous layer was extracted with EtOAc (2×200 mL) and the organic layerswere combined and dried (Na₂SO₄). The solvents were removed in vacuo,and the residue was washed with Methanol to give tert-butyl4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (14.0 g,68.1%) as a solid which was used crude in the subsequent reaction.

LCMS (Method F): m/z 282 (M+H)⁺ (ES⁺), at 2.05 min, UV active

tert-butyl 4-hydroxy-4-(1-methyl-1H-pyrrol-2-yl)piperidine-1-carboxylate(0.5 g, 1.7 mmol) was dissolved in 1,4 dioxane (30 mL) at rt and thereaction mixture was cooled to 0° C. under nitrogen, HCl in dioxane (15mL, 4M sol.) was slowly added. The reaction module was stirred at rt for6 h. the solvents were removed in vacuo, and the residue purified bytrituration from pentane (10 mL) and diethyl ether (10 mL) to giveIntermediate 48, 4-(1-methyl-1H-imidazol-2-yl)piperidin-4-ol (0.2 g,62.5%) as brown solid. The data for the title compound are m Table 2.

Procedure for the Preparation of Intermediate 50,4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine Hydrochloride Salt

tert-Butyl4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (3.0 g,10.6 mmol) was dissolved in DMF (50 mL) at rt and the reaction mixturewas cooled to 0° C. under nitrogen, NaH (0.64 g, 16.0 mmol, 60%dispersion in oil) was added. The reaction mixture was stirred at 0° C.for 1 hr and then methyliodide (1.6 g, 128 mmol) was added dropwise. Thereaction mixture was warmed it and stirred for 10 h, then quenched withwater (50 mL). The reaction mixture was extracted with EtOAc (3×200 mL),and the organic layers were combined and dried (Na₂SO₄). The solventswere removed in vacuo, and the residue was purified by columnchromatography (normal phase, silica, 60-120 mesh, gradient 0% to 50%EtOAc in Hexane) to give tert-butyl4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.3 g,41.3%) as an pale yellow solid.

LCMS (Method F): m/z 296 (M+H)⁺ (ES⁺), at 2.36 min, UV active

tert-Butyl4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.3 g,3.3 mmol) was dissolved in 1,4 dioxane (30 mL) at rt and the reactionmixture was cooled to 0° C. under nitrogen, HCl in dioxane (15 mL, 4Msol.) was slowly added. The reaction mixture was stirred at rt for 6 h,the solvents were removed in vacuo, and the residue purified bytrituration from pentane (10 mL) and diethyl ether (10 mL) to giveIntermediate 50, 4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidine (0.80g, 94.1%) as an off white solid. The data for the title compound are inTable 2.

Procedure for the Preparation of Intermediate 111, benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate

(2S,4R)-1-Boc-4-hydroxy pyrrolidine-2-carboxylic acid methyl ester (25g, 101.93 mmol) and imidazole (34.687 g, 509.5 mmol) were dissolved inDMF (100 mL) and reaction cooled to 0° C. tert-Butyldimethylsilylchloride was then added (36.86 g, 244.56 mmol), reaction warmed to RTand stirred for 18 h. Volatiles removed on rotavap and reaction mixturediluted with DCM (250 mL). Mixture washed with H₂O (2×250 mL), combinedaqueous layers washed with DCM (250 mL), combined organic layers washedwith saturated NH₄Cl_((aq)) (250 mL) and brine (250 mL) and passedthrough Biotage Phase separator. Volatiles removed under vacuum to give(2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-carboxylicadd methyl ester (35.812 g, 99%).

LCMS (Method D): m/z 260 (M+H−Boc)⁺ (ES⁺), at 2.64 min, UV inactive

(2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-carboxylicadd methyl ester (42.7 g, 118.76 mmol) was dissolved in THF (100 mL) andreaction cooled to 0° C. Lithium aluminium hydride was then added (120mL of 1.0M solution in THF, 120.0 mmol) and reaction stirred at 0° C.for 1 h. Reaction quenched with H₂O (4.5 mL), 15% NaOH solution (4.5 mL)and H₂O (13.5 mL) and filtered through a celite plug. Volatiles removedunder vacuum to give (2S,4R)-1-Boc-4-tert-butyldimethylsilylether-pyrrolidine-2-hydroxy methyl (30.320 g, 77%).

LCMS (Method D): m/z 232 (M+H−Boc)⁺ (ES⁺), at 2.00 min, UV inactive

(2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-hydroxymethyl (10.050 g, 30.362 mmol) was dissolved in DCM (100 mL) andDess-Martin Periodinane (15.371 g, 36.253 mmol) was added. Reaction wasslimed at rt for 2 hours, then volatiles removed on rotavap and crudeproduct loaded directly onto Biotage SNAP column (100 g) forpurification (10% to 50% EtOAc in n-hexane gradient) yielding(2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-carbaldehyde(2.150 g, 22%).

To a suspension of sodium hydride (135 mg of 60% dispersion in oil,3.338 mmol) in THF (8 mL) at 0° C. was added triethylphosphono acetate(0.665 mL, 3.338 mmol). After 10 mins,(2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-carbaldehyde(1.002 g, 3.034 mmol) in THF (2 mL) was added and reaction stirred at 0°C. for 30 mins. Volatiles removed on rotavap and reaction mixturediluted with DCM (20 mL). Mixture washed with H₂O (2×20 mL), combinedaqueous layers washed with DCM (20 mL), combined organic layers washedwith brine (20 mL) and passed through Biotage Phase separator. Volatilesremoved under vacuum and crude mixture loaded onto Biotage SNAP column(100 g) and purified by column chromatography (0 to 30% EtOAc in Hexane)yielding tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylateas a colourless oil (545 mg, 45%).

LCMS (Method D): m/z 300 (M+H−Boc)⁺ (ES+), at 2.85 min, UV inactive.

To a solution of potassium tert-butoxide (421 mg, 3.753 mmol) and ethylcyanoacetate (0.399 mL, 3.753 mmol) in EtOH (5 mL) was added tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)siyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate(500 mg, 1.251 mmol) and reaction stirred at 78° C. for 18 h. AcOH wasadded (0.200 mL) and volatiles removed on rotavap Reaction mixturediluted with DCM (50 mL) and washed with H₂O (2×50 mL), combined aqueouslayers washed with DCM (50 mL), combined organic layers washed withbrine (50 mL) and passed through Biotage Phase separator. Volatilesremoved under vacuum and crude mixture loaded onto Biotage SNAP column(100 g) and purified by column chromatography (0 to 30% EtOAc in Hexane)yielding diethyl3-[(4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]-2-cyanopentanedioateas a yellow oil (587 mg, 89%).

To a solution of sodium chloride (71 mg, 1.212 mmol) and DMSO (0.040 mL,2.204 mmol) in H₂O (3 mL) was added diethyl3-[(4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]-2-cyanopentanedioate(565 mg, 1.102 mmol) and reaction stirred at 145° C. for 2 h. Ice waterwas added was added (50 mL) followed by EtOAc (50 mL) and organic layerwashed with H₂O (2×50 mL). Combined organic layers washed with brine (50mL) and passed through Biotage Phase separator. Volatiles removed undervacuum and crude mixture loaded onto Biotage SNAP column (50 g) andpurified by column chromatography (0 to 30% EtOAc in Hexane) yieldingtert-butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-cyano-4-ethoxy-4-oxobutan-2-yl)pyrrolidine-1-carboxylateas a yellow oil (351 mg, 72%).

LCMS (Method D): m/z 341 (M+H−Boc)⁺ (ES+), at 2.77 min, UV inactive

To a flask containing NiEnCat™ (65 g wet beads, 0.25 equiv.) was addedtert-butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-cyano-4-ethoxy-4-oxobutan-2-yl)pyrrolidine-1-carboxylate(8.700 g, 19.7 mmol) in EtOH (75 mL) and reaction stirred at 78° C.under a hydrogen balloon atmosphere for 96 h. Reaction mixture filteredover a celite plug and volatiles removed under vacuum, the erode mixturewas loaded onto Biotage SNAP column (340 g) and purified by columnchromatography (2.5 to 10% MeOH in DCM) yielding tert-butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-oxopiperidin-4-yl)pyrrolidine-1-carboxylateas a yellow oil (4.665 g, 59%).

LCMS (Method D): m/z 399 (M+H)⁺ (ES+), at 1.90 min, UV inactive

To a solution of tert-butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-oxopiperidin-4-yl)pyrrolidine-1-carboxylate(1.850 g, 4.648 mmol) THF (30 mL) was added borane:tetrahydrofuran (9.3mL of 1.0M solution in THF, 9.300 mmol) at 0° C. and reaction stirred at60° C. for 30 mins. Reaction cooled to rt and quenched with MeOH (10 mL)and volatiles removed on rotavap. Reaction mixture diluted with DCM (100mL) and washed with 1M NaOH_((aq)) (2×100 mL), combined aqueous layerswashed with DCM (100 mL), combined organic layers washed with brine (250mL) and passed through Biotage Phase separator. Volatiles removed undervacuum yielding tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(piperidin-4-yl)pyrrolidine-1-carboxylateas a yellow oil (1.830 g, >99%).

LCMS (Method D): m/z 285 (M+H−Boc)⁺ (ES+), at 3.00 min, UV inactive

To a solution of tert-butyl(2S,4R)-4-([tert-butyl(dimethyl)silyl]oxy)-2-(piperidin-4-yl)pyrrolidine-1-carboxylate(1.830 g, 4.766 mmol) in DCM (20 mL) was added diisopropylethylamine(1.814 mL, 10.484 mmol) and benzyl chloroformate (0.816 mL, 5.719 mmol)at 0° C. Reaction warmed to rt and stirred for 18 h. Reaction mixturediluted with DCM (100 mL) and washed with 1M NaOH_((aq)) (2×100 mL),combined aqueous layers washed with DCM (100 mL), combined organiclayers washed with brine (250 mL) and passed through Biotage Phaseseparator. Volatiles removed under vacuum and crude mixture loaded ontoBiotage SNAP column (100 g) and purified by column chromatography (10 to40% EtOAc in Hexane) yielding benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]piperidine-1-carboxylateas a colourless oil (700 mg, 28%).

To a solution of benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]piperidine-1-carboxylate(0.780 g, 1.504 mmol) in THF (5 mL) was added tetrabutylammoniumfluoride (1.800 mL of 1.0 M THF solution, 1.800 mmol) and reactionstirred at rt for 1 h. Reaction mixture diluted with DCM (100 mL) andwashed with H₂O (2×100 mL), combined aqueous layers washed with DCM (100mL), combined organic layers washed with brine (250 mL) and passedthrough Biotage Phase separator. Volatiles removed under vacuum yieldingIntermediate 111, benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate,as a colourless oil (500 mg, 82%). The data for the title compound arein Table 2.

Procedure for the Preparation of Intermediate 112, tert-butyl(2S,4S)-4-fluoro-2-(piperidin-4-yl)pyrrolidine-1-carboxylate

Benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate(100 mg, 0.247 mmol) was dissolved in DCM (1 mL) at −40° C. and DAST wasadded (0.049 mL, 0.371 mmol). Reaction warmed to rt and stirred for 2 h.Reaction mixture diluted with DCM (25 mL) and washed with saturatedNaHCO_(3(aq)) (2×25 mL), combined aqueous layers washed with DCM (25mL), combined organic layers washed with brine (25 mL) and passedthrough Biotage Phase separator. Volatiles removed under vacuum to yieldbenzyl4-[(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl]piperidine-1-carboxylate(0.090 g, 90%).

LCMS (Method D): m/z 307 (M+H−Boc)⁺ (ES+), at 2.31 min, UV inactive

To a solution of benzyl4-[(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl]piperidine-1-carboxylate(0.060 g, 0.221 mmol) dissolved in EtOH (2 mL) was added 10% Pd/C (10mg) and 1,4 cyclohexadiene (0.147 mL, 1.530 mmol) and reaction stirredat 70° C. for 1 h. Reaction filtered through a celite plug and volatilesremoved under vacuum to yield Intermediate 112, tert-butyl(2S,4S)-4-fluoro-2-(piperidin-4-yl)pyrrolidine-1-carboxylate (55 mg,92%). The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 113, tert-butyl(2S)-4,4-difluoro-2-(piperidin-4-yl)pyrrolidine-1-carboxylate

Oxalyl chloride (0.065 mL, 0.741 mmol) was dissolved in DCM (1 mL) at−78° C. and DMSO was added (0.100 mL). After 5 minutes at −78° C.,benzyl4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate(200 mg, 0.494 mmol) was added in DCM (2 mL) followed by triethylamine(0.345 mL, 2.47 mmol) after a further 5 mins at −78° C. Reaction warmedto rt and stirred for 30 mins. React on mixture diluted with DCM (25 mL)and washed with saturated NaHCO_(3(aq)), (2×25 mL), combined aqueouslayers washed with DCM (25 mL), combined organic layers washed withbrine (25 mL) and passed through Biotage Phase separator. Volatilesremoved under vacuum to yield benzyl4-[(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidin-2-yl]piperidine-1-carboxylate(0.170 g, 85%).

LCMS (Method D): m/z 303 (M+H−Boc)⁺ (ES+), at 2.15 min, UV inactive

benzyl4-[(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidin-2-yl]piperidine-1-carboxylate(170 mg, 0.422 mmol) was dissolved in DCM (1 mL) at −78° C. and DAST wasadded (0.167 mL, 1.267 mmol). Reaction warmed to rt and stirred for 18h. Reaction mixture diluted with DCM (25 mL) and washed with saturatedNaHCO_(3(aq)) (2×25 mL), combined aqueous layers washed with DCM (25mL), combined organic layers washed with brine (25 mL) and passedthrough Biotage Phase separator. Volatiles removed under vacuum to yieldbenzyl4-[(2S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl]piperidine-1-carboxylate(0.070 g, 39%).

LCMS (Method D): m/z 325 (M+H−Boc)⁺ (ES+), at 2.41 min, UV inactive

To a solution of benzyl4-[(2S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl]piperidine-1-carboxylate(0.067 g, 0.158 mmol) dissolved in EtOH (2 mL) was added 10% Pd/C (10mg) and 1,4 cyclohexadiene (0.105 mL, 1.105 mmol) and reaction stirredat 70° C. for 1 h. Reaction filtered through a celite plug and volatilesremoved under vacuum to yield Intermediate 113, tert-butyl(2S)-4,4-difluoro-2-(piperidin-4-yl)pyrrolidine-1-carboxylate (30 mg,65%). The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 126, tert-butyl(2S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate

To 1-tert-butyl 2-methyl (2R)-4,4-difluoropyrrolidine-1,2-dicarboxylate(2 g, 7.5 mmol) in THF (20 mL) was added lithium borohydride solution inTHF (2.0 M, 7.5 mL, 15 mmol) at 0° C. and the reaction was warmed to RTand stirred for 2 h. The reaction was quenched by the portion-wiseaddition of saturated aqueous NaHCO₃, and once effervescence had ceased,the mixture was concentrated to remove THF. The aqueous mixture waspartitioned between saturated aqueous NaHCO₃ and DCM (×2), the organicphases were passed through a phase separator and concentrated to affordthe crude tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.98g, >100%) as an oil.

LCMS (Method C): m/z 260 (M+Na)⁺ (ES⁺), at 1.09 min, UV inactive.

To a solution of tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 42mmol) in DCM (10 mL) and triethylamine (1.5 mL, 11 mmol) at 0° C. wasadded MsCl (0.42 mL, 5.4 mmol) portion-wise. The mixture was stirred at0° C. for 100 min, then partitioned between ice cold saturated aqueousNaHCO₃ and ice cold DCM (×2), the organic phases were passed through aphase separator and concentrated to afford the crude tert-butyl(2R)-4,4-difluoro-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate(1.56 g, >100%) as an oil.

LCMS (Method C): m/z 336 (M+Na)⁺ (ES⁺), at 1.28 min, UV inactive.

To a solution of tert-butyl(2R)-4,4-difluoro-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate(1.55 g, 4.0 mmol) in THF (15 mL) at 0° C. was added LiBHEt₃ solution inTHF (1.0 M, 9.8 mL, 9.8 mmol), portion-wise over 10 min. The mixture wasthen stirred for 3 days, a Hewing the cooling bath to expire. Themixture was cooled back to 0° C., quenched by the addition of H₂O, thenconcentrated to remove THF The aqueous mixture was partitioned betweensaturated aqueous NaHCO₃ and DCM (×2), the organic phases were passedthrough a phase separator and concentrated to afford the crudeIntermediate 125, tert-butyl(2S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate (0.89 g, 82%) as anoil. The data for the the compound are in Table 2.

Procedure for the Preparation of Intermediate 126, tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

(R)-1-tert-Butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (1.00 g,4.111 mmol) was dissolved in DCM (10 mL) at −78° C. and DAST was added(1.629 mL, 12.332 mmol). Reaction warmed to rt and stirred for 2 h.Reaction mixture diluted with DCM (100 mL) and washed with saturatedNaHCO_(3(aq)) (2×100 mL), combined aqueous layers washed with DCM (100mL), combined organic layers washed with brine (25 mL) and passedthrough Biotage Phase separator. Solvent were removed in vacuo to givean orange oil (0.957 g, 90%).

To (R>1-tert-Butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate(500 mg, 1.885 mmol) in THF (5 mL) was added lithium borohydride as a2.0M solution in THF (1.90 mL, 3.80 mmol) at 0° C. and the reaction waswarmed to RT and stirred for 1 h. The solvents were removed in vacuo,and the reaction mixture diluted with DCM (50 mL) and washed withsaturated NaHCO_(3(aq)) (2×50 mL), combined aqueous layers washed withDCM (50 mL), combined organic layers washed with brine (50 mL) andpassed through Biotage Phase separator. Volatiles removed under vacuumyielding Intermediate 126, tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (452 mg,92%).

Procedure for the Preparation of Intermediate 132,3-(piperidin-4-yl)-1,3-oxazinan-2-one Hydrochloride

tert-Butyl 4-oxopiperidine-1-carboxylate (0.796 g, 4.00 mmol) and3-aminopropan-1-ol (0.330 g, 4.4 mmol) were mixed in CH₂Cl₂ (20 mL) atrt, AcOH (0.68 mL, 12.0 mmol) was added and stirred for 3 h. STAB (2.34g, 10.0 mmol) was added and the reaction mixture was stirred undernitrogen at ft overnight. The reaction mixture was quenched with theaddition of NaHCO₃ (sat aq.) (40 mL) extracted with CH₂Cl₂ (4×45 mL) andthe combined organic layers were washed with brine, then dried overMgSO₄ and filtered. The solvents were removed in vacuo to give crudetert-butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carboxylate (1.03 g,4.00 mmol) which was used without purification.

LCMS (Method B): m/z 259 (M+H)⁺ (ES+), at 0.24 min, UV inactive.

tert-Butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carboxylate (1.03 g,4.00 mmol). CDI (1.36 g, 8.4 mmol) and DBU (0.24 mL, 1.60 mmol) weredissolved in THF (40 mL), the mixture heated to reflux and maintainedfor 72 h. The solvents were removed in vacuo and the residue purified bycolumn chromatography [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60Å, 50 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl4-(2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (0.60 g, 53%) as acolourless oil.

LCMS (Method B): m/z 307 (M+Na)⁺ (ES+), at 0.16 min, UV inactive.

tert-Butyl 4-(2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (0.60 g,211 mmol) was dissolved in CH₂Cl₂ (21 mL), 4 M hydrogen chloride indioxane (2.64 mL, 10.5 mmol) added and the reaction mixture stirred atrt overnight. The precipitate was collected by filtration, washed withCH₂Cl₂ (2×20 mL) and dried to give Intermediate 132,3-(piperidin-4-yl)-1,3-oxazinan-2-one hydrochloride (0.352 g, 76%) as acolourless solid. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 161, ethyl2-(4-oxopiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateHydrochloride

Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.985 g, 5.00 mmol) and1,4-dioxa-8-azaspiro[4.5]decane (0.715 g, 5.00 mmol) were mixed inCH₂Cl₂ (50 mL) at rt, AcOH (0.31 mL, 5.50 mmol) was added and stirredfor 3 h. STAB (2.65 g, 12.5 mmol) was added and the reaction mixture wasstirred under nitrogen at rt overnight. The reaction mixture wasquenched with the addition of NaHCO₃ (sat aq.) (40 mL) extracted withCH₂Cl₂ (4×45 mL) and the combined organic layers were washed with brine,then dried over MgSO₄ and filtered. The solvents were removed in vacuoto give crude ethyl2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylateas a mixture of diastereomers which was used without furtherpurification.

LCMS (Method D): m/z 325 (M+H)⁺ (ES+), at 1.11 min and 1.16 min, UVinactive.

Crude ethyl2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate(1.62 g, 5.00 mmol) was dissolved in THF (10 mL), water (10 mL) andconcentrated hydrochloric acid (10 mL) were added and the mixturestirred at rt overnight. The solvents were removed in vacuo and theresidue tritiated from Et₂O to give Intermediate 151, ethyl2-(4-oxopiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylatehydrochloride (1.30 g, 82%) as a colourless solid. The data for thetitle compound are in Table 2.

Procedure for the Preparation of Intermediate 164,4-(1,3-thiazol-4-yl)piperidine Hydrobromide

Aqueous sodium carbonate solution (2M) and 1,4-dioxane were bothdegassed by passing a stream of nitrogen through a fritted glass tubeinto the liquids for 15 min. Benzyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(250 mg, 0.73 mmol), 4-bromo-1,3-thiazole (119 mg, 0.73 mmol),[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg, 0.044mmol), degassed aqueous sodium carbonate solution (2M, 1.1 mL, 2.2 mmol)and degassed 1,4-dioxane (3 mL) were placed into a nitrogen flushedtube, sealed and heated under pressure at 90° C. for 2.5 h. The cooledreaction mixture was diluted with H₂O and extracted with EtOAc. Theorganic phase was passed through a phase separator and concentrated ontoflash silica (15 mL) The resulting powder was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63μm, 60 Å], 40 mL per min, 65% Et₂O in isohexane isochratic) to givebenzyl 4-(1,3-thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (173mg, 79%).

LCMS (Method C): m/z 301 (M+H)⁺ (ES⁺), at 1.46 min, UV active.

A solution of benzyl4-(1,3-thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.50mmol) in EtOAc (10 mL) was hydrogenated over 10% palladium on carboncatalyst at 100 bar pressure and at 50° C. at a flow rate of 1 mL/minusing a H-Cube apparatus. The solution was concentrated to give benzyl4-(1,3-thiazol-4-yl)piperidine-1-carboxylate (143 mg, 95%).

LCMS (Method A): m/z 303 (M+H)⁺ (ES⁺), at 1.92 min, UV active.

A solution of benzyl 4-(1,3-thiazol-4-yl)piperidine-1-carboxylate (127mg, 0.42 mmol) in AcOH (1 mL) and 48% aqueous HBr (1 mL) was stirred atRT overnight. The mixture was then concentrated and the residueazeotroped with toluene to give Intermediate 164,4-(1,3-thiazol-4-yl)piperidine hydrobromide (160 mg, >100%). The datafor the title compound is in Table 2.

Procedure for the Preparation of Intermediate 172,(1R,5S)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonan-7-one

(1S,3S,5S)-Cyclohexane-1,3,5-triol (1.0 g, 6.0 mmol) and phenylboronicacid (0.72 g, 6.0 mmol) were dissolved in toluene (35 mL) and heated atreflux at 120° C. for 16 h. The reaction mixture was concentrated togive the crude(1R,5S,7R)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonan-7-ol (1.43 g,87%) as a solid, which was used immediately. (1R,5S,7R)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonan-7-ol (1.4 g, 6.4 mmol)was dissolved in DCM (50 mL). Sodium acetate (1.31 g, 16 mmol) andpyridinium chlorochromate (12.9 g, 11 mmol) were added and the reactionmixture was stirred for 16 h. The reaction mixture was filtered throughCelite, and the filtrate was concentrated to give the crude productwhich was recrystallization from DCM:hexane (1:4) to give Intermediate172, (1R,5S)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonan-7-one (0.65 g,38%) as a solid. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 174,4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidineTrifluoroacetate Salt

A solution of tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (150 mg,0.63 mmol) in THF (5 mL) was cooled in ice water and treated with 60%sodium hydride suspension in mineral oil (30 mg, 0.75 mmol). The mixturewas stirred in ice for 30 min then at RT for 1.5 h before adding methyliodide (0.118 mL, 1.9 mmol) and stirring at RT overnight. The mixturewas quenched with a drop of H₂O then concentrated to remove THF. Theresidue was partitioned between sat. aqueous NaHCO₃ and DCM (×2), theorganic phase was passed through a phase separator and concentrated togive the crude tert-butyl(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine-1-carboxylate (110 mg,69%) as an oil.

LCMS (Method C): m/z 274 (M+Na)⁺ (ES⁺), at 1.35 min, UV inactive.

A solution of the crude tert-butyl(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine-1-carboxylate (110 mg,0.44 mmol) In DCM (2 mL) and TFA (2 mL) was stirred at RT for 40 minthen diluted with toluene and concentrated. The residue was azeotropedwith toluene (×2) to give the crude(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine trifluoroacetate salt asan oil (172 mg, >100%).

LCMS (Method C): m/z 152 (M+H)⁺ (ES⁺), at 0.73 min, UV inactive.

The crude (2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidinetrifluoroacetate salt (172 mg, assumed 0.44 mmol) was dissolved in DMF(5 mL). To the solution was added DIPEA (0.38 mL, 2.2 mmol). AcOH (0.036mL, 0.66 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (0.087 g, 0.44mmol) and STAB (0.276 g, 1.3 mmol) in that order. The mixture wasstirred at RT for 2 days, then concentrated to remove DMF. The residuewas partitioned between sat. aqueous NaHCO₃ and DCM (×2) and the organicphase was passed through a phase separator and concentrated to give thecrude tert-butyl4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.241 g, >100%) as an oil.

LCMS (Method C): m/z 335 (M+H)⁺ (ES⁺), at 1.43 min, UV inactive.

A solution of the crude tert-butyl4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.241 g, assumed 0.44 mmol) in DCM (2 mL) and TFA (2 mL) was stirred atRT for 45 min then diluted with toluene and concentrated. The residuewas azeotroped with toluene (×2) to give the crude Intermediate 174,4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidinetrifluoroacetate salt as an oil.

The data for the title compound is in Table 2

Procedure for the Preparation of Intermediate 179,1-[(2R)-4,4-difluoro-1-(piperidin-4-yl)pyrrolidin-2-yl]ethanolTrifluoroacetate Salt

A solution of tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (150 mg,0.63 mmol) In DCM (5 mL) was cooled in Ice water and treated withDess-Martin Periodinane (402 mg, 0.95 mmol). The cooling bath wasremoved and the mixture was stirred at RT for 3 h. Sat. aqueous NaHCO₃(5 mL), sat. aqueous sodium thiosulphate (5 mL) and EtOAc (10 mL) wereadded and the mixture was stirred vigorously for 30 min. The phases wereseparated and the aqueous was re-extracted with EtOAc. The combinedorganic phases were passed through a phase separator and concentrated togive the crude aldehyde, which was immediately dissolved in THF (5 mL),cooled to −78° C. and treated with methylmagnesium bromide in ether (3M,0.42 mL, 1.3 mmol). The mixture was removed from the cooling bath,stirred for 2.75 h and then quenched by the addition of sat. aqueousNH₄Cl. The mixture was concentrated to remove THF and then partitionedbetween sat. NH₄Cl and DCM (×2). The organic phase was passed through aphase separator and concentrated onto flash silica (10 mL). Theresulting powder was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å], 30 mL per min, 20to 50% EtOAc in isohexane, to give tert-butyl(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (0.106 g,67%) as an oil.

LCMS (Method C): m/z 152 (M−BOC+H)⁺, 196 (M−tBu+H)⁺ (ES⁺), at 1.24 min,UV inactive.

A solution of the tert-butyl(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (102 mg,0.41 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at RT for 30 minthen diluted with toluene and concentrated. The residue was azeotropedwith toluene to give the crude1-[(2R)-4,4-difluoropyrrolidin-2-yl]ethanol trifluoroacetate salt as agum. Used immediately.

LCMS (Method C): m/z 152 (M+H)⁺ (ES⁺), at 0.27 min, UV inactive.

The crude 1-[(2R)-4,4-difluoropyrrolidin-2-yl]ethanol trifluoroacetatesalt from above (assumed 0.41 mmol) was dissolved in DMF (5 mL). To thesolution was added DIPEA (0.38 mLm, 2.0 mmol), AcOH (0.035 mL, 0.61mmol), tert-butyl 4-oxopiperidine-1-carboxylate (0.081 g, 0.41 mmol) andSTAB (0.258 g, 1.2 mmol) in that order. The mixture was stirred at RTfor 3 days, then concentrated to remove DMF The residue was azeotropedwith toluene, dissolved in MeOH and concentrated onto flash silica (5mL). The resulting powder was purified by column chromatography (normalphase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å], 30 mL permin 0 to 15% Solvent A in DCM, where Solvent A is 10% of (7 M NH3/MeOH)in MeOH) to give tert-butyl4-[(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.301 g, >100%) as an oil.

LCMS (Method C): m/z 335 (M+H)⁺ (ES⁺), at 1.41 min, UV inactive.

A solution of tert-butyl4-[(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.301 g, assumed 0.41 mmol) in DCM (2 mL) and TFA (2 mL) was stirred atRT for 30 min then diluted with toluene and concentrated. The residuewas azeotroped with toluene to give the crude Intermediate 179,1-[(2R)-4,4-difluoro-1-(piperidin-4-yl)pyrrolidin-2-yl]ethanoltrifluoroacetate salt as an oil (0.553 g, >100%). The data for the titlecompound are in Table 2

Procedure for the Preparation of Intermediate 215,4-(1H-tetrazol-1-yl)piperidine Hydrochloride Salt

Triethylorthoformate (3.5 g, 23 mmol), tert-butyl4-aminopiperidine-1-carboxylate (0.80 g, 3.9 mmol) and sodium azide(1.52 g, 23 mmol) were dissolved in acetic acid (50 mL). The resultingreaction mixture was stirred at 100° C. for 6 h, then cooled to RT. Thevolatiles were removed by concentration and the residue was partitionedbetween H₂O (100 mL) and ethyl acetate (150 mL). The aqueous layer wasfurther extracted with ethyl acetate (2×100 mL), the combined organiclayers were dried (Na₂SO₄), and the solvent was removed by concentrationto give the crude product, which was triturated with diethyl ether togive tert-butyl 4-(1H-tetrazol-1-yl) piperidine-1-carboxylate (0.51 g,9%) as a solid.

LCMS (Method F): m/z 254 (M+H)⁺ (ES⁺), at 1.92 min, weakly UV active.

tert-Butyl 4-(1H-tetrazol-1-yl)piperidine-1-carboxylate (0.51 g, 2.0mmol) was dissolved in 1, 4-dioxane (10 mL). A solution of HCl in 1,4-dioxane (4M, 5 mL, 20 mmol) was added dropwise and the resultingmixture was stirred at RT for 16 h. The solvents were removed byconcentration and the residue was purified by triturating with diethylether (3×10 mL) to give Intermediate 215, 4-(1H-tetrazol-yl)piperidinehydrochloride (0.30 g, 97%) as a solid. The data for the title compoundare in Table 2.

Procedure for the Preparation of Intermediate 218,4-(1-cyclopropyl-1H-tetrazol-6-yl)piperidine Hydrochloride Salt

1-(tert-Butoxycarbonyl) piperidine-4-carboxylic acid (2.0 g, 8.7 mmol)and cyclopropylamine (0.6 mL, 8.7 mL) were dissolved in DMF (45 mL).HATU (3.3 g, 8.7 mmol) was added at room temperature followed by DIPEA(3.1 mL 17 mmol). The reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was diluted with cold water (250 mL) andextracted with EtOAc (3×100 mL). The combined organic layers were dried(Na₂SO₄) and concentrated to give the crude product, which was purifiedby column chromatography (Normal phase, Neutral silica gel, 60-120 mesh,0 to 35% EtOAC in hexanes) to give tert-butyl4-(cyclopropylcarbamoyl)piperidine-1-carboxylate (1.5 g, 64%) as asolid.

LCMS (Method F): m/z 269 (M+H)⁺ (ES⁺), at 1.80 min, weakly UV active.

tert-Butyl 4-(cyclopropylcarbamoyl)piperidine-1-carboxylate (1.5 g, 5.6mmol) and triphenyl phosphine (2.9 g, 11 mmol) were dissolved n THF (160mL). DIAD (2.26 g, 11 mmol) was added at room temperature over 15 minTrimethylsilyl azide (1.3 g, 11 mmol) was added and the reaction mixturewas allowed to stir at room temperature for 24 h. The reaction mixturewas diluted with water (250 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give thecrude product, which was purified by column chromatography (Normalphase, Neutral silica gel, 60-120 mesh, 0 to 30% EtOAC in hexane) togive tert-butyl4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (400 mg, 24%)as a solid.

LCMS (Method F): m/z 294 (M+H)⁺ (ES⁺), at 1.96 min, weakly UV active.

tert-Butyl 4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidine-1-carboxylate(400 mg, 1.4 mmol) was dissolved in dioxane (5 mL). A solution of HCl indioxane (4M, 5 mL, 20 mmol) was added at 0° C. and the mixture wasstirred at room temperature for 5 h. The solvent was removed byconcentration and the residue was triturated with diethyl ether (10 mL)to give Intermediate 218 4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidinehydrochloride (260 mg, 98%) as a solid. The data for the title compoundare in Table 2.

Procedure for the Preparation of Intermediate 193,1-(piperidin-4-yl)pyrrolidine-2,5-dione Trifluoroacetate Salt

Succinimide (0.098 g, 1.0 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (0.221 g, 1.10 mmol andtriphenylphosphine (0.314 g, 1.20 mmol) were dissolved in THF (5 mL)then treated with diisopropyl azodicarboxylate (0.236 mL, 1.20 mmol) andstirred at RT overnight. The reaction mixture was concentrated ontoflash silica (5 mL) The resulting powder was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63μm, 60 Å], 30 mL per min, 20% to 100% EtOAc in Isohexane) to givetert-butyl 4-(2,5-dioxopyrrolidin-1-yl)piperidine-1-carboxylate (0.253g, 90%) as a solid.

LCMS (Method C): m/z 305 (M+Na)⁺ (ES⁺), at 1.11 min, UV inactive

A solution of tert-butyl4-(2,5-dioxopyrrolidin-1-yl)piperidine-1-carboxylate (0.141 g, 0.50mmol) in DCM (3 mL) and TFA (3 mL) was stirred at RT for 30 min thendiluted with toluene and concentrated. The residue was azeotroped withtoluene to give Intermediate 193,1-(piperidin-4-yl)pyrrolidine-2,5-dione trifluoroacetate salt as a gum.Used immediately. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 229, ethyl2-([2,4′-bipiperidin]-1′-yl)-6-azaspiro[3.4]octane-6-carboxylate

To a solution of 2-bromopyridine (10.0 g, 63.3 mmol) in dry THF (60 mL),n-BuLi (79.1 mL, 2.5 M in hexane, 126 mmol) was slowly added at −78° C.After stirring at this temperature for 30 min, tert-butyl4-oxopiperidine-1-carboxylate (13.8 g, 69.6 mmol) In THF (40 mL) wasslowly added. The reaction temperature was gradually brought to roomtemperature and stirred for 2 h. After cooling to 0° C., the reactionmixture was carefully quenched with ice cold water (50 mL). Afterremoval of the volatiles, the aq layer was extracted with ethyl acetate(3×50 mL). The organic layers were combined and washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography [normal phase, silica gel (100-200 mesh),gradient 0% to 30% ethyl acetate in hexane] to give tert-butyl4-hydroxy-4-(pyridin-2-yl)piperidine-1-carboxylate (11.4 g, 65%) as ayellow oil.

¹H-NMR (400 MHz; CDCl₃) δ: 1.48 (s, 9H), 1.56-1.63 (m, 2H), 1.90-2.0 (m,2H), 3.25-3.46 (m, 2H), 4.05-4.22 (m, 2H), 5.29 (br.s., 1H), 7.20-7.25(m, 1H), 7.32 (d, J=8.0, Hz, 1H), 7.73 (dt, J=1.6, 8.4 Hz, 1H), 8.53 (d,J=4.8 Hz, 1H).

To a solution of tert-butyl4-hydroxy-4-(pyridin-2-yl)piperidine-1-carboxylate (11.4 g, 41.0 mmol)in pyridine (100 mL). POCl₃ (5.7 mL, 61.5 mmol) was added and stirred atroom temperature for 20 h. After removal of pyridine in vacuo, thereaction mixture was quenched with aq NaOH (10%, 30 mL) and extractedwith chloroform (2×30 mL). The organic layers were combined, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography [normal phase, silica gel (100-200 mesh),gradient 0% to 30% ethyl acetate in hexane] to give tert-butyl3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (2.3 g, 21%) as ayellow oil.

¹H-NMR (400 MHz; CDCl₃) δ: 1.48 (s, 9H), 2.81-2.70 (m, 2H), 3.60-3.70(m, 2H), 4.10-4.19 (m, 2H), 6.58-6.62 (m, 1H), 7.11-7.19 (m, 1H), 7.36(d, J=7.88 Hz, 1H), 7.62-7.66 (m, 1H), 8.55 (d, J=4.4 Hz, 1H).

To a solution of tert-butyl3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (2.3 g, 8.84 mmol)in CH₂Cl₂ (20 mL), PtO₂ (200 mg, 0.88 mmol) was added and the reactionmixture was stirred at room temperature for 2 d under Ha atmosphere. Thereaction mixture was filtered through a pad of celite, washed with MeOHand concentrated in vacuo. The residue was purified by flash columnchromatography [normal phase, silica gel (100-200 mesh), gradient 0% to15% MeOH in DCM having 0.1% aq ammonia] to give tert-butyl[2,4′-bipiperidine]-1′-carboxylate (105 g, 44%) as a colorless oil.

¹H-NMR (400 MHz; CDCl₃) δ: 1.30-1.40 (m, 1H), 1.48 (s, 9H), 1.60-1.91(m, 8H), 2.45-2.55 (m, 2H), 2.58-2.75 (m, 4H), 3.24-3.31 (m, 1H),4.14-4.24 (m, 2H).

To a solution of tert-butyl [2,4′-bipiperidine]-1′-carboxylate (1.05 g,3.91 mmol) In THF (5 mL), Cbz-OSu (975 mg, 3.91 mmol) in THF (5 mL) wasadded and stirred at room temperature for 2 h. The reaction mixture wasquenched with water (20 mL) and the aq layer was extracted with ethylacetate (2×20 mL). The organic layers were combined and washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The residuewas purified by flash column chromatography [normal phase, silica gel(100-200 mesh), gradient 0% to 20% ethyl acetate in hexane] to give1-benzyl 1′-(tert-butyl) [2,4′-bipiperidine]-1,1′-dicarboxylate (840 mg,53%) as a colorless oil.

¹H-NMR (400 MHz; CDCl₃) δ: 1.44 (s, 9H), 1.50-1.63 (m, 2H), 1.68-1.92(m, 4H), 1.95-2.14 (m, 2H), 2.55-2.80 (m, 2H), 2.81-2.95 (m, 4H),2.98-3.10 (m, 1H), 3.75-4.24 (m, 3H), 5.11 (s, 2H), 7.34-7.37 (m, 5H).]

To a solution of 1-benzyl 1′-(tert-butyl)[2,4′-bipiperidine]-1,1′-dicarboxylate (840 mg, 2.1 mmol) in CH₂Cl₂ (10mL), HCl in dioxane (10 mL, 4 M) was slowly added at 0° C. and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was quenched with saturated NaHCO₃ (20 mL) and the aq layer wasextracted with CH₂Cl₃ (2×20 mL). The organic layers were combined, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby flash column chromatography [normal phase, silica gel (100-200 mesh),gradient 0% to 15% MeOH in DCM having 0.1% aq ammonia] to give benzyl[2,4′-bipiperidine]-1-carboxylate (570 mg, 90%) as a colorless stickysolid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.70 (m, 6H), 1.71-1.98 (m, 4H),2.46-2.63 (m, 2H), 2.68-2.73 (m, 1H), 3.03-3.18 (m, 1H), 3.65-3.80 (m,2H), 3.86-4.16 (m, 2H), 5.11 (s, 2H), 7.34-7.37 (m, 5H).

To a solution of benzyl [2,4′-bipiperidine]-1-carboxylate (520 mg, 1.72mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (305 mg, 1.55mmol) in CH₂Cl₂ (15 mL), Ti(O^(i)Pr)₄ (1.6 mL, 5.16 mmol) was added andstirred at 0° C. for 40 min. To this reaction mixture NaBH₄ (1.1 g, 5.16mmol) was added and stirring continued at this temperature for 2 h. Thereaction mixture was quenched with water (20 mL) and the aq layer wasextracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby prep-HPLC (reverse phase, X BRIDGE, C-18, 19×250 mm, 5μ, gradient 68%to 90% ACN in water containing 0.1% NH₄OH, 214 nm, RT: 7.45 min forIsomer-1 and 8.37 min for Isomer-2 to give ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate Isomer 1, (120 mg, 15%) andethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate Isomer-2, (160 mg, 19%)as colorless sticky solids.

Isomer-1:

LCMS (Method L): m/z 484 (M+H)⁺ (ES+), at 5.70 min, UV active.

¹H-NMR (400 MHz; CDCl₃) δ: 1.10-1.32 (m, 6H), 1.36-1.95 (m, 14H),2.00-2.18 (m, 2H), 2.52-3.05 (m, 4H), 3.20-3.45 (m, 4H), 3.87-4.18 (m,4H), 5.11 (s, 2H), 7.30-7.35 (m, 5H),

Isomer-2:

LCMS (Method L): m/z 484 (M+H)⁺ (ES+), at 5.61 min, UV active.

¹H-NMR (400 MHz; CDCl₃) δ: 1.10-1.32 (m, 6H), 1.35-1.53 (m, 5H),1.62-1.80 (m, 5H), 1.81-1.97 (m, 4H), 2.00-2.18 (m, 2H), 2.52-3.00 (m,4H), 3.18-3.52 (m, 4H), 3.88-4.20 (m, 4H), 5.11 (s, 2H), 7.32-7.37 (m,5H).

To a solution of a mixture of isomers of ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.0 g, 2.06 mmol) in MeOH (20mL), 10% Pd on charcoal (320 mg, 50% wet) was added and the reactionmixture was stirred at rt for 16 h under H₂ atmosphere. The reactionmixture was filtered through a pad of celite, washed with MeOH andconcentrated in vacuo, and triturated with pentane to give Intermediate229, ethyl2-([2,4′-bipiperidin]-1′-yl)-6-azaspiro[3.4]octane-6-carboxylate (445mg, 92%) as a colorless liquid. The data for the title compound are inTable 2.

Procedure for the Preparation of Intermediate 243, tert-butyl1-(piperidin-4-yl)-1,3-dihydro-2H-isoindole-2-carboxylate

To a solution of isoindoline-1-carboxylic add hydrochloride (5.0 g, 25.0mmol) in methanol (60 mL), SOCl₂ (2.7 mL, 37.5 mmol) was slowly added at0° C. and the reaction mixture was stirred at room temperature for 16 h.After completion, the reaction mixture was concentrated in vacuo. Theresidue was triturated with diethyl ether to give methylisoindoline-1-carboxylate hydrochloride (4.9 g, 92%) as an off whitesold. The residue was used for the next step without furtherpurification.

¹H-NMR (400 MHz; DMSO-d₆) δ: 3.81 (s, 3H), 4.52-4.63 (m, 2H), 5.70 (s,1H), 7.44-7.50 (m, 4H), 9.77 (br.s., 2H).

To a solution of methyl isoindoline-1-carboxylate hydrochloride (4.9 g,23.0 mmol) in DCM (50 mL), Et₃N (9.9 mL, 69.0 mmol) and (Boc)₂O (8.0 mL,34.0 mmol) were sequential added at 0° C. The reaction mixture wasstirred at room temperature for 12 h. The reaction mixture was quenchedwith water (20 mL). After separating the organic layer, the aq layer wasextracted with CH₂Cl₂ (3×15 mL). The organic layers were combined andwashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The crude residue was purified by flash column chromatography [normalphase, silica gel (100-200 mesh), gradient 10% to 30% ethyl acetate inhexane] to give 2-(tert-butyl) 1-methyl isoindoline-1,2-dicarboxylate(6.5 g, 90%) as a colorless liquid.

¹H-NMR (400 MHz; CDCl₃) δ: 1.52 (S, 9H), 3.75 (S, 3H), 4.65-4.85 (m,2H), 5.45 (s, 1H), 7.25-7.43 (m, 4H).

To a solution 2-(tert-butyl) 1-methyl isoindoline-1,2-dicarboxylate (6.5g, 23.0 mmol) in THF (60 mL), LAH (2M, 11.5 mL, 23.0 mmol) was slowlyadded at 0° C. and stirred for 30 min. After completion, the reactionmixture was quenched with sat aq Na₂SO₄ (20 mL). The reaction mixturewas filtered through a pad of celite and washed with ethyl acetate (100mL), dried (Na₂SO₄) and concentrated in vacuo to give tert-butyl1-(hydroxymethyl)isoindoline-2-carboxylate (5.2 g, 91%) as an off whitesolid. The crude residue was used for the next step without furtherpurification.

¹H-NMR (400 MHz; CDCl₃) δ: 1.52 (s, 9H), 3.70-3.78 (m, 1H), 3.98-4.03(m, 1H), 4.80-4.89 (m, 1H), 4.70-4.85 (m, 2H), 522 (br.s, 1H), 7.25-7.40(m, 4H).

To a solution of tert-butyl 1-(hydroxymethyl)isoindoline-2-carboxylate(5.2 g, 20.0 mmol) in DCM (100 mL), Dess-Martin periodinane (27 g, 62.0mmol) was added portion wise at 0° C. and stirred at room temperaturefor 48 h After completion, the reaction mixture was filtered through apad of celite and washed with diethyl ether (3×20 mL) The filtrate waswashed with sat aq NaHCO₃ solution, brine, dried (Na₂SO₄) andconcentrated in vacuo to give tert-butyl1-formylisoindoline-2-carboxylate (4.5 g, 88%) as a brown liquid. Thecrude residue was used for the next step without further purification.

¹H-NMR (400 MHz; CDCl₃) δ: 1.48 (s, 9H), 4.65-4.90 (m, 2H), 5.29-5.35(s, 1H), 7.25-7.35 (m, 4H), 9.51 (s, 1H).

To a solution of NaH (674 mg, 18.2 mmol) In THF,trimethylphosphonoacetate (3.3 mL, 16.2 mmol) was added at −78° C. Afterstirring for 1 h at −78° C., tert-butyl1-formylisoindoline-2-carboxylate (4.5 g, 18.2 mmol) was slowly addedand the reaction mixture was a Bowed to 0° C. After completion, thereaction mixture was quenched with sat aq NH₄Cl solution (10 mL) and theaqueous layer was extracted with ethyl acetate (3×20 mL). The organiclayers were combined, dried (Na₂SO₄) and concentrated in vacuo to givetert-butyl(E)-1-(3-methoxy-3-oxoprop-1-en-1-yl)isoindoline-2-carboxylate (5.2 g,92%) as a brown liquid. The residue was used for the next step withoutfurther purification.

MS (ESI +ve): 304

To a solution of tert-butyl(E)-1-(3-methoxy-3-oxoprop-1-en-1-yl)isoindoline-2-carboxylate (52 g,17.2 mmol) in MeCN (20 mL), Cs₂CO₃ (11.1 g, 34.4 mmol) was added portionwise at room temperature. After stirring for 20 min, methyl cyanoacetate(3.0 mL, 34.4 mmol) was slowly added and the reaction mixture wasstirred at 70° C. for 16 n After completion, the reaction mixture wasfiltered through a pad of celite and thoroughly washed with hexane (3×20mL). The filtrate was concentrated in vacuo to give dimethyl3-(2-(tert-butoxycarbonyl)isoindolin-1-yl)-2-cyanopentanedioate) (5.5 g,cr) as a brown sticky solid. The crude residue was used for the nextstep without further purification.

MS (ESI +ve): 403

To a solution of dimethyl3-(2-(tert-butoxycarbonyl)isoindolin-1-yl)-2-cyanopentanedioate) (1.6 g,erode) in DMSO (15 mL), LiCl (500 mg, 11.7 mmol) was added followed byaddition of water (0.1 mL, cat.) and the reaction mixture was stirred at135° C. for 16 h. After completion, the reaction mixture was quenchedwith water (20 mL) and the aq layer was extracted with diethyl ether(3×20 mL). The organic layers were combined, dried (Na₂SO₄) andconcentrated in vacuo to give tert-butyl1-(1-cyano-4-methoxy-4-oxobutan-2-yl)isoindoline-2-carboxylate (1.5 g,cr) as a brown semisolid. The crude residue was used for the next stepwithout further purification.

MS (ESI +ve): 345

To a solution of tert-butyl1-(1-cyano-4-methoxy-4-oxobutan-2-yl)isoindoline-2-carboxylate (300 mg,0.8 mmol) in MeOH (30 mL), Raney-Ni (0.30 g. wet) was added and thereaction mixture was heated to 50° C. for 2 h under H₂ atmosphere at 50psi. Then the reaction temperature was increased to 70° C. and stirredfor 3 h After completion, the reaction mixture was filtered through apad of celite, washed with MeOH (25 mL) and concentrated in vacuo. Theresidue was triturated with diethyl ether (30 mL) to give tert-butyl1-(2-oxopiperidin-4-yl)isoindoline-2-carboxylate (0.21 g, 76%) as abrown solid.

MS (ESI +ve): 317

To a solution of tert-butyl1-(2-oxopiperidin-4-yl)isoindoline-2-carboxylate (210 mg, 0.60 mmol) inTHF (5 mL), BH₃-DMS (0.5 mL, 6.60 mmol) was slowly added at 0° C. andthe reaction mixture was stirred at 78° C. for 8 h. After cooling at 0°C., the reaction mass was quenched with methanol (0.5 mL) followed bywater (1 mL). To the crude reaction mass 5% MeOH/DCM (30 mL) was addedand filtered. The filtrate was concentrated in vacuo. The residue wastriturated with diethyl ether (20 mL) to give tert-butyl1-(piperidin-4-yl)isoindoline-2-carboxylate, Intermediate 243 (200 mg,99%) as a brown solid. The data for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 247,4-(2H-1,2,3-triazol-2-yl)piperidine

tert-Butyl 4-hydroxy piperidine-1-carboxylate (0.500 g, 2.4 mmol) wasdissolved in CH₂Cl₂ then DMAP (0.302 g, 2.4 mmol) and methane sulfonylchloride (0.284 g, 2.48 mmol) added dropwise at 0° C. The resultingreaction mixture was stirred at RT for 6 h then partitioned between H₂O(70 mL) and CH₂Cl₂ (70 mL), the aqueous layer was further extracted withCH₂Cl₂ (2×70 mL), the organic layers were combined, dried (Na₂SO₄),filtered and the solvent removed in vacuo to give crude tert-butyl4-((methylsulfonyl) oxy) piperidine-1-carboxylate (0.520 g, 75.0%) as awhite solid which was used directly without any further purification.

¹H-NMR (400 MHz; DMSO) δ: 1.23 (d, J=9.38 Hz, 2H) 1.54-1.66 (m, 4H)1.86-1.96 (m, 2H) 2.35 (S, 1H) 2.85-3.00 (m, 2H) 3.18 (d, J=5.42 Hz, 5H)3.54-3.67 (m, 4H) 4.83 (S, 1H).

1H-1,2,3-Triazole (0.098 g, 14 mmol) was dissolved in DMF (5 mL), NaH(0.037 g, 1.5 mmol) was added and stirred at 0° C. for 30 min.tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.400 g, 1.4mmol) was added and stirred at 150° C. for 1 h. The reaction mixture waspartitioned between H₂O (50 mL) and EtOAc (50 mL), the aqueous layer wasfurther extracted with EtOAc (2×50 mL), the organic layers werecombined, dried (Na₂SO₄), filtered and the solvent was removed in vacuoto give crude tert-butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.350 g, 97.0%) as a colorless gum which wasused directly without any further purification.

LCMS (Method F): m/z 253 (M+H)⁺ (ES+), at 1.95 min, UV active.

tert-Butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.500 g,1.9 mmol) was dissolved in 1,4-dioxane (10 mL) followed by drop wiseaddition of HCl in 1,4-dioxane (5 mL, 4M). The resulting reactionmixture was stirred at 25° C. for 16 h, the solvents were removed invacuo and the residue was purified by triturating with diethyl ether(3×10 mL) to give 4-(2H-1,2,3-triazol-2-yl)piperidine hydrochloride,Intermediate 247, (0.290 g, 96.3%) as a light white sold. The data forthe title compound are in Table 2.

Procedure for the Preparation of Intermediate 256,4-(5-methyl-1H-tetrazol-1-yl)piperidine Hydrochloride

5-Methyl-2H-tetrazole (0.500 g, 5.9 mmol) and fed-butyl4-bromopiperidine-1-carboxylate (1.29 g, 4.8 mmol) were dissolved inDMF. K₂CO₃ (1.64 g, 11.8 mmol) was added, the resulting reaction mixturewas stirred at 100° C. for 6 h then partitioned between H₂O (100 mL) andethyl acetate (150 mL). The aqueous layer was further extracted withethyl acetate (2×100 mL), the organic layers were combined, dried(Na₂SO₄), filtered and the solvent was removed in vacuo. The residue waspurified by combi-flash column chromatography (normal phase, neutralsilica gel, 60-120 mesh, 10 to 20% EtOAc in hexane) to give tert-butyl4-(5-methyl-1H-tetrazol-1-yl)piperidine-1-carboxylate (0.280 g, 34.6%)as a white solid.

¹H-NMR (400 MHz, DMSO) δ: 1.43 (s, 9H), 1.73-1.88 (m, 2H), 2.01 (br. s.,2H), 2.68-2.75 (m, 3H), 2.88-2.91 (m, 2H), 4.03-4.10 (m, 2H) 4.60-4.70(m, 1H).

tert-Butyl 4-(5-methyl-1 W-tetrazol-1-yl) piperidine-1-carboxylate(0.280 g, 1.04 mmol) was dissolved in 1, 4-dioxane (10 mL) followed bydrop wise addition of HCl in 1, 4-dioxane (5 mL, 4M). The resultingreaction mixture was stirred at 25° C. for 16 h, the solvents wereremoved in vacuo and the residue was purified by triturating withdiethyl ether (3×10 mL) to give 4-(5-methyl-1H-tetrazol-1-yl)piperidinehydrochloride, Intermediate 255 (0.170 g, 97.6%) as a white solid. Thedata for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 258, give(R)-2-(4,4-difluoro-1-(piperidin-4-yl)pyrrolidin-2-yl)propan-2-olHydrochloride

To a solution of 1-(tert-butyl) 2-methyl(R)-4,4-difluoropyrrolidine-1,2-dicarboxylate (500 mg, 1.89 mmol) mdioxane (15 mL), HCl in dioxane (4 M, 15 mL) was slowly added at 0° C.and stirred at room temperature for 3 h. The reaction mixture wasconcentrated in vacuo and the residue was triturated with hexane (10mL). This residue was basified with aq sat NaHCO₃ (10 mL) andconcentrated. To the crude reaction mass CDM (30 mL) was added andfiltered. The titrate was concentrated in vacuo to give methyl(R)-4,4-difluoropyrrolidine-2-carboxylate (2, 320 mg, 84%) as a brownliquid. This crude residue was used for the next step without furtherpurification.

¹H-NMR (400 MHz, CDCl₃) δ: 1.40-1.51 (m, 1H), 2.58-2.84 (m, 3H),3.52-3.62 (m, 1H), 3.84 (s, 3H), 4.40-4.52 (m, 1H).

To a solution of methyl (R)-4,4-difluoropyrrolidine-2-carboxylate (200mg, 1.21 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (240 mg,1.21 mmol) in methanol (20 mL), 10% palladium on carbon (300 mg, 50%wet) was added and the reaction mixture was stirred under H₂ (1 atm) atroom temperature for 24 h. After completion, the reaction mixture wasfiltered through a pad of celite, thoroughly washed with methanol andconcentrated in vacuo to give tert-butyl(R)-4-(4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl)piperidine-1-carboxylate(400 mg, 95%) as a colour less liquid.

¹H-NMR (400 MHz, CDCl₃) δ: 1.32-1.45 (m, 1H), 1.45 (s, 9H), 1.61-1.80(m, 4H), 2.39-2.49 (m, 1H), 2.50-2.83 (m, 2H), 3.19 (s, 3H), 3.35-3.49(m, 2H), 3.61-3.82 (m, 3H), 3.94-4.05 (m, 1H).

To a solution tert-butyl(R)-4-(4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl)piperidine-1-carboxylate(375 mg, 1.07 mmol) in THF (10 mL), MeMgBr (3M, 1.07 mL, 3.21 mmol) wasslowly added at 0° C. and stirred for 4 h at room temperature. Aftercompletion, the reaction mixture was quenched with sat aq NH₄Cl solution(10 mL) and the aqueous layer was extracted with ethyl acetate (3×10mL). The organic layers were combined, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude residue was purified by flash columnchromatography [normal phase, silica gel (100-200 mesh), gradient 10% to30% ethyl acetate in hexane] to give tert-butyl(R)-4-(4,4-difluoro-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate(240 mg, 64%) as a colorless liquid.

¹H-NMR (400 MHz. CDCl₃) δ: 1.11 (s, 3H), 1.21 (s, 3H), 1.21-1.40 (m,2H), 1.49 (s, 9H), 1.61-1.80 (m, 2H), 2.15-2.30 (m, 3H), 2.50-2.83 (m,3H), 3.02-3.23 (m, 2H), 4.09-4.30 (m, 2H), O—H not observed.

To a solution of(R)-4-(4,4-difluoro-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate(240 mg, 0.69 mmol) in dioxane (10 mL), HCl in dioxane (4 M, 10 mL) wasslowly added at 0° C. and stirred at room temperature for 2 h. Thereaction mixture was concentrated in vacuo and the residue trituratedwith hexane (10 mL). To the crude reaction mass CH₂Cl₂ (30 mL) was addedand filtered. The titrate was concentrated in vacuo to give(R)-2-(4,4-difluoro-1-(piperidin-4-yl)pyrrolidin-2-yl)propan-2-olhydrochloride, Intermediate 268 (150 mg, 87%) as a brown liquid. Thedata for the title compound are in Table 2.

Procedure for the Preparation of Intermediate 282, tert-butyl(2R)-2-(dimethylcarbamoyl)piperidine-1-carboxylate

(R)-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.500 g, 2.18mmol) was dissolved in anhydrous DCM (8 mL) and the reaction mixture wascooled to 0° C. under nitrogen.1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (0.628 g, 3.275mmol), hydroxybenzotriazole (0.334 g, 2.183 mmol), N-methylmorpholine(1.104 g, 10.915 mmol) and dimethylamine hydrochloride (0.356 g, 4.36mmol) was added and the reaction mixture was stirred at rt undernitrogen overnight. The reaction mixture was diluted with DCM (20 mL)and washed with sat. NaHCO₃ (aq) (20 mL) and sat. NaCl (aq) (20 mL). Theorganic layer was passed through a Biotage Phase Separator Cartridge andthe solvents were removed in vacuo. The residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g 40-63μm, 60 Å, 25 mL per min, gradient 0% to 10% MeOH/DCM]) to givetert-butyl (2R)-2-(dimethylcarbamoyl)piperidine-1-carboxylate,Intermediate 282, (0241 g, 43%) as an amber oil. The data for the titlecompound are in Table 2

Procedure for the Preparation of Intermediate 296, tert-butyl(2R)-2-(fluoromethyl)pyrrolidine-1-carboxylate

(2R)-(+)-1-Boc-2-pyrolidinemethanol (0.300 g, 1.49 mmol) was dissolvedin DCM (8 mL) and cooled under nitrogen to −78° C.N,N-Diethylaminosulfur trifluoride (0.360 g 2.24 mmol) was added to thereaction mixture dropwise, the reaction mixture was stirred at −78° C.under nitrogen for 4 h and then warmed to it overnight. The reactionmixture was quenched by addition of sat. NaHCO₃ (aq) (20 mL) andextracted with DCM (2×15 mL), the organic layers were combined and driedby passing through a Biotage Phase Separator Cartridge and the solventswere removed in vacuo. The residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 10 g 40-63 μm, 60 Å, 12 mLper min, gradient 0% to 4% MeOH/DCM]) to give tert-butyl(2R)-2-(fluoromethyl)pyrrolidine-1-carboxylate, Intermediate 296, (0.104g, 34%), as an amber oil. The data for the title compound are in Table 2

Procedure for the Preparation of Intermediate 286, Methyl(4S)-1,3-thiazolidine-4-Carboxylate Hydrochloride

(S)-3-Boc-thiazolidine-4-carboxylic add (1.00 g, 4.29 mmol) wasdissolved in anhydrous DMF (4 mL), potassium carbonate (2.372 g, 17.16mmol) and iodomethane (0.730 g, 5.14 mmol) were added. The reactionmixture was stirred at rt under nitrogen overnight. The solvents wereremoved in vacuo and the residue was dissolved in EtOAc (40 mL) andwashed with water (3×20 mL) and sat. NaCl (aq) (20 mL), dried (MgSO₄).The solvents were removed in vacuo give 3-tert-butyl-4-methyl(4S)-1,3-thiazolidine-3,4-dicarboxylate, Intermediate 286, (0.812 g,77%) as a pale yellow oil. The data for the title compound are in Table2

Procedure for the Preparation of Intermediate 297, tert-butyl(2R)-2-(difluoromethyl)pyrrolidino-1-carboxylate

DMSO (0.696 g, 8.94 mmol) was added dropwise to a solution of oxalylchloride (0.566 g 2.93 mmol) in anhydrous DCM (12 mL) at −78° C. undernitrogen. The reaction mixture was stirred at −78° C. under nitrogen (or15 min then a solution of (2R)-(+)-1-Boc-2-pyrrolidinemethanol (0.600 g,2.98 mmol) in anhydrous DCM (4 mL) was added dropwise. The reactionmixture was stirred at −78° C. under nitrogen for 15 min then Et₃N (1.06g, 11.92 mmol) was added and the reaction mixture was stirred at 0° C.under nitrogen for 1 h. The reaction mixture was quenched with sat.NaHCO₃ (aq) (20 mL) and extracted with DCM (2×20 mL), the organic layerswere combined and dried by passing through a Biotage Phase SeparatorCartridge and the solvents were removed in vacuo. The residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 10 g 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 4% MeOH/DCM])to give tert-butyl(2R)-2-formylpyrrolidine-1-carboxylate (0.436 g, 73%).

tert-butyl(2R)-2-formylpyrrolidine-1-carboxylate (0.435 g, 2.19 mmol)was dissolved in anhydrous DCM (8 mL) and cooled under nitrogen to −78°C. N,N-Diethylaminosulfur trifluoride (0.528 g, 3.28 mmol) was added tothe reaction mixture dropwise, the reaction mixture was stirred at −78°C. under nitrogen for 3 h and then warmed to rt overnight. The reactionmixture was quenched by addition of sat. NaHCO₃ (aq) (20 mL) andextracted with DCM (2×15 mL), the organic layers were combined and driedby passing through a Biotage Phase Separator Cartridge and the solventswere removed in vacuo. The residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 10 g 40-63 μm, 60 Å, 12 mLper min, gradient 0% to 4% MeOH/DCM]) to give tert-butyl(2R)-2-(difluoromethyl)pyrrolidine-1-carboxylate, Intermediate 297,(0.217 g, 45%) as an amber oil. The data for the title compound are inTable 2

General Synthetic Procedures for Intermediates Route 1 Typical Procedurefor the Preparation of Piperidines Via Suzuki Reaction, Hydrogenationand Boc-Deprotection as Exemplified by the Preparation of Intermediate30, 6-(piperidin-4-yl)-1,2,4-thiadiazole

2-5-Bromo-1,2,4-thiadiazole (108 mg, 0.65 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)carboxylate(200 mg, 0.65 mmol) and Cs₂CO₃ (632 mg, 1.94 mmol) were dissolved inDioxane:water (10:2 mL). The reaction mixture was degassed for 30 minsfollowed by addition of PdCl₂dppf (24 mg, 0.03 mmol) then stirred for 16h at 90° C. The reaction mixture was partitioned between H₂O (80 mL) andEtOAc (50 mL), the aqueous layer was further extracted with EtOAc (2×50mL), the organic layers were combined, dried (Na₂SO₄), solvents wereremoved in vacuo and the residue was purified by column chromatography(normal phase silica, mesh size: 60-120, 18% to 20% EtOAc in Hexane) togive tert-butyl4-(1,2,4-thiadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (158 mg,92.0%) as an off white solid.

LCMS (Method F): m/z 212 (M+H−56)⁺ (ES+), at 2.37 min, UV active

tert-Butyl4-(1,2,4-thiadiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg,0.74 mmol) was dissolved in MeOH (15 mL) and 10% Pd/C (20 mg) was added.The reaction mixture was purged with H₂ gas and stirred at 25° C. for 8h under H₂ pressure. The reaction mixture was filtered through celite,the residue was washed with MeOH, and the solvents were removed in vacuoand the residue was purified by column chromatography (normal phasesilica, mesh size: 60-120, 20% to 24% EtOAc in Hexane) to givetert-butyl 4-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (150 mg,74.6%) as a dark green gum.

LCMS (Method F): m/z 214 (M+H)⁺ (ES+), at 2.14 min, UV active

tert-Butyl 4-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (150 mg,0.56 mmol) was dissolved in 1,4-dioxane (5 mL), HCl in dioxane (10 mL,3.0M solu.) was added dropwise and the reaction was stirred at 30° C.for 16 h. Solvents were removed in vacuo and the residue was purified bytriturating with diethyl ether (3×3 mL) to give Intermediate 30,5-(piperidin-4-yl)-1,2,4-thiadiazole (102 mg, 89.5%) as a dark greengum. The data for the title compound are in Table 2.

Route 2 Procedure for the Preparation of Intermediate 34,4-(1,5-dimethyl-1H-imidazol-2-yl)-1,2,3,6-tetrahydropyridine

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(2.0 g, 6.55 mmol), 2-bromo-1,5-dimethyl-1H-imidazole (1.13 g, 6.45mmol) and CsF (2.9 g, 1.85 mmol) were dissolved in DME:MeOH (2:1, 30mL). The reaction mixture was degassed for 5 mins, then Pd(PPh₃)₄ (73mg, 0.064 mmol) was added and the resulting reaction mixture was stirredfor 5 h at 100° C. The reaction mixture was partitioned between H₂O (100mL) and EtOAc (100 mL), the aqueous layer was further extracted withEtOAc (2×100 mL), the organic layers were combined, dried (Na₂SO₄) andthe solvents were removed in vacuo. The residue was purified by columnchromatography (normal silica, mesh size: 60-120, 13% to 17% Ethylacetate in Hexane) to give tert-butyl4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1 g, 55%) as a yellow gum.

LCMS (Method F): m/z 278 (M+H)⁺ (ES⁺), at 1.70 min, UV active

tert-Butyl4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.0 g, 3.81 mmol) was dissolved in 1,4-dioxane (20 mL) followed bydropwise addition of HCl in 1,4-dioxane (20 mL, 3M solu.). The resultingreaction mixture was stirred at 30° C. for 16 h the solvents wereremoved in vacuo and the residue was purified by triturating withdiethyl ether (3×5 ml) to give Intermediate 34,4-(1,5-dimethyl-H-imidazo-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride(0.5 g, 65%) as a white solid. The data for the the compound are inTable 2.

Route 3 Typical Procedure for the Preparation of Piperidines Via SuzukiReaction, Hydrogenation and Boc-deprotection as Exemplified by thePreparation of Intermediate 65, 3-(piperidin-4-yl)pyridin-2(1H)-oneHydrochloride

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(25 g, 10.0 mmol), 3-iodo-2-methoxypyridine (8.21 g, 26.0 mmol) andK₂CO₃ (4.3 g, 31.8 mmol) were dissolved in 1-4 dioxane (10 ml) and water(5 mL). The reaction mixture was degassed using N₂ for 15 min; Pd-132(0.376 g, 0.53 mmol) was added and the reaction mixture was stirred at80° C. for 2 h. The reaction mixture was diluted with water (50 mL),extracted with EtOAc (2×100 mL), the organic layers were combined, dried(N₂SO₄), solvent was removed in vacuo and crude product was purified bycolumn chromatography (Normal phase, 80-120 mesh silica, 0 to 20% EtOAcin Hexane) to give tert-butyl2-ethoxy-3′,8′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (2.0 g,69.0%) as off white solid.

LCMS (Method F): m/z 291 (M+H)⁺ (ES+), at 2.39 min, UV active

tert-Butyl 2-methoxy-3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate(1.89 g, 6.51 mmol) was dissolved in MeOH (10 mL) and 10% Pd/C (0.2 g)was added. The reaction mixture was purged with H₂ gas and stirred at rtfor 12 h under H₂. The reaction mixture was filtered through celite andsolvents were removed in vacuo to give tert-butyl4-(2-methoxypyridin-3-yl) piperidine-1-carboxylate (0.91 g, 47.9%) as acolorless gum.

LCMS (Method F): m/z 293 (M+H)⁺ (ES+), at 2.50 min, UV active

tert-Butyl 4-(2-methoxypyridin-3-yl) piperidine-1-carboxylate (0.200 g,0.6 mmol) was dissolved in 1,4-dioxane (4.0 mL) and water (2.0 ml) andconc. HCl was added, the reaction mixture was stirred for 10 h at 100°C. The solvents were removed in vacuo and the residue was trituratedwith acetone (3×10 ml) to give Intermediate 6,3-(piperidin-4-yl)pyridin-2(1H)-one hydrochloride (0.100 g, 82.8%) as abrown solid. The data for the title compound are in Table 2.

Route 4 Typical Procedure for the Preparation of Piperidines Via SuzukiReaction, Hydrogenation and Boc-deprotection as Exemplified by thePreparation of Intermediate 66, 2-Methoxy-3-(piperidin-4-yl)pyridineHydrochloride

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,8-dihydropyridine-1(2H)-carboxylate(2.5 g, 10.0 mmol), 3-iodo-2-methoxypyridine (8.21 g, 26.0 mmol) andK₂CO₃ (4.3 g, 31.8 mmol) were dissolved in 1-4 dioxane (10 ml) and water(5 mL). The reaction mixture was degassed using N₂ for 15 min; Pd-132(0.376 g, 0.53 mmol) was added and the reaction mixture was stirred at80° C. for 2 h. The reaction mixture was diluted with water (50 mL),extracted with EtOAc (2×100 mL), the organic layers were combined, dried(N₂SO₄), solvent was removed in vacuo and crude product was purified bycolumn chromatography (Normal phase, 60-120 mesh silica, 0 to 20% EtCAcin Hexane) to give tert-butyl2-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (2.0 g,69.0%) as off white solid.

LCMS (Method F): m/z 291 (M+H)⁺ (ES+), at 2.39 min, UV active

tert-Butyl 2-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate(1.89 g, 6.51 mmol) was dissolved in MeOH (10 mL) and 10% Pd/C (0.2 g)was added. The reaction mixture was purged with H₂ gas and stirred at rtfor 12 h under H₂. The reaction mixture was filtered through celite andsolvents were removed in vacuo to give tert-butyl4-(2-methoxypyridin-3-yl) piperidine-1-carboxylate (0.91 g, 47.9%) as acolorless gum.

LCMS (Method F): m/z 293 (M+H)⁺ (ES+), at 2.50 min, UV active

tert-Butyl 4-(2-methoxypyridin-3-yl)piperidine-1-carboxylate (0.8 g, 2.7mmol) was stirred in HCl in 1,4-dioxane (4.0 mL, 4.0M solu.) for 10 h atrt. The solvents were removed in vacuo and the residue was triturated byacetone (3×10 mL) to give Intermediate 66,2-methoxy-3-(piperidin-4-yl)pyridine hydrochloride (0.135 g, 25.7%) aswhite solid. The data for the title compound are in Table 2.

Route 5 Typical Procedure for the Preparation of Piperidines ViaHydrogenation as Exemplified by the Preparation of Intermediate 69,3,4′-bipiperidin-2-one

3-(Piperidin-4-yl-1,6-dihydropyridin-2-ol (0.5 g, 2.8 mmol) wasdissolved in MeOH (10 mL) and PtO₂ (0.2 g) was added. The reactionmixture was purged with H₂ gas and stirred at it for 12 h under H₂ gas.The reaction mixture was filtered through celite and the solvents wereremoved in vacuo to give Intermediate 69, 3,4′-bipiperidin-2-one (0.4 g,78.3%) as a brown gum. The data for the title compound are in Table 2.

Route 6 Typical Procedure for the Preparation of Pyrrolidines Via ViaReductive Amination and Boc-deprotection as Exemplified by thePreparation of Intermediate 127, Mixture of Diastereomers of Ethyl2-(4-[(2S)pyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

(S)-tert-Butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxylate (1.24 g, 6.29mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-8-carboxylate (1.60 g, 6.29mmol) were dissolved in DMF (15 mL) at it and acetic acid (0.54 mL, 9.44mmol) was added. The reaction mixture was stirred at rt for 3 h. STAB(2.67 g, 12.8 mmol) was then added and the reaction mixture was stirredovernight under nitrogen at rt. The solvents were removed in vacuo, andthe residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 340 g, 40-63 μm, 80 Å, 80 mL per min,gradient 0% to 10% 7N NH₃ in MeOH in DCM]) to give an inseparablemixture of isomers of ethyl2-{4-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-8-azaspiro[3.4]octane-6-carboxylate(2.48 g, 93%) as a yellow solid.

LCMS (Method D): m/z 438 (M+H)⁺ (ES⁺), at 2.38 min, UV inactive.

A mixture of diastereomers of ethyl2-(4-[(2S-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylate(0.6 g, 1.4 mmol) was dissolved in 1,4-dioxane (10 mL) and treateddropwise with HCl in 1,4-dioxene (4M, 15 mL, 60 mmol). The resultingreaction mixture was stirred at 25° C. for 16 h, the solvents wereremoved and the residue was purified by triturating with diethyl ether(3×10 mL) to give a mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Intermediate 127 as a solid (0.45 g, 97%). The data for the titlecompound are in Table 2.

Route 7 Typical Procedure for the Preparation of Piperidines ViaReductive Amination, Boc-Deprotection, Urea Formation, andHydrogenolysis as Exemplified by the Preparation of Intermediate 137,1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-one

Benzyl 4-oxopiperidine-1-carboxylate (0.932 g, 4.00 mmol) and tert-butyl(3-aminopropyl)carbamate (0.766 g, 4.4 mmol) were mixed in CH₂Cl₂ (20ml) at rt, AcOH (0.68 mL, 12.0 mmol) was added and stirred for 3 h. STAB(2.59 g, 12.0 mmol) was added and the reaction mixture was stirred undernitrogen at rt overnight. The reaction mixture was quenched with theaddition of NaHCO₃ (sat aq.) (40 ml) extracted with CH₂Cl₂ (4×45 ml) andthe combined organic layers were washed with brine, then dried overMgSO₄ and filtered. The solvents were removed in vacuo and the residuepurified by column chromatography [Biotage SNAP cartridge KP-sil 25 g,40-63 μm, 60 Å, 50 mL per min, gradient 0% to 10% MeOH in DCM]) to givebenzyl4-({3-[(tert-butoxycarbonyl)amino]propyl}amino)piperidine-1-carboxylate(1.54 g, 98%) as a colourless oil.

LCMS (Method B): m/z 392 (M+H)⁺ (ES+), at 1.73 min, UV active.

Benzyl4-({3-[(tert-butoxycarbonyl)amino]propyl}amino)piperidine-1-carboxylate(1.54 g, 3.92 mmol) was dissolved in CH₂Cl₂ (19.5 mL), 4 M hydrogenchloride in dioxane (4.90 mL, 19.0 mmol) added and the reaction mixturestirred at rt overnight. The solvents were removed in vacuo, the residuewashed with CH₇Cl₂ (2×20 mL) and dried to give crude benzyl4-[(3-aminopropyl)amino]piperidine-1-carboxylate dihydrochloride (1.41g, 99%) as an off-white solid.

LCMS (Method B): m/z 292 (M+H)⁺ (ES+), at 1.46 min, UV active.

Crude benzyl 4-[(3-aminopropyl)amino]piperidine-1-carboxylatedihydrochloride (1.41 g, 3.88 mmol), CDI (0.778 g, 4.80 mmol) andpyridine (0.24 mL, 12.0 mmol) were dissolved in THF (39 mL), the mixtureheated to reflux and maintained for 18 h. The solvents were removed invacuo and the residue purified by column chromatography [Biotage SNAPcartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min, gradient 0% to 10%MeOH in DCM]) to give benzyl4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-6-carboxylate (0.82 g,65%) as a colourless solid.

LCMS (Method B): m/z 318 (M+H)⁺ (ES+), at 2.62 min, UV active.

Benzyl 4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate(0.82 g, 2.59 mmol) was dissolved in EtOH (100 mL) and passed through a10% Pd/C cartridge using a H-Cube set at 50° C., 40 Bar H₂ at 1 mL/min.The eluted solution was concentrated in vacuo to give Intermediate 137,1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-one (0.470 g, 99%) as acolourless solid. The data for the title compound are in Table 2.

Route 8 Typical Procedure for the Preparation of Piperidines ViaReductive Amination, and Boc-Deprotection as Exemplified by thePreparation of Intermediate 139,(2S)—N-methyl-1-(piperidin-4-yl)pyrrolidine-2-carboxamide

(S)—N-methylpyrrolidine-2-carboxamide (0.5 g, 3.8 mmol), NEt₃ (1.5 mL,11.0 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (0.38 g, 3.9 mmol)and ZnCl₂ (0.15 g, 4.5 mmol) were dissolved in MeOH (15 mL) undernitrogen and stirred for 1 h at 50-60° C. NaCNBH₃ (0.16 g, 0.67 mmol)was added portion wise at 0-10° C. and the mixture stirred for 3 hrs atroom temperature. The reaction mixture was partitioned between EtOAc(2×100 mL) and water (50 mL), the organic layers were combined, dried(Na₂SO₄), filtered, the solvent was removed in vacuo and the crudeproduct was purified by column chromatography (normal phase silica, 0 to20% EtOAc in hexane) to give tert-butyl (S)-4-(2-(methylcarbamoyl)pyrrolidin-1-yl) piperidine-1-carboxylate (0.3 g, 25.0%) as a lightbrown liquid.

TLC observation: RF value: 0.5 (EA: Hex, 5:5).

LCMS (Method G): m/z 312 (M+H)⁺ (ES+), at 1.61 min, UV inactive.tert-Butyl (S)-4-(2-(methylcarbamoyl) pyrrolidin-1-yl)piperidine-1-carboxylate (0.3 g, 0.96 mmol) was stirred in HCl in1,4-dioxane (5.00 mL) solution for 10 hrs at room temperature. Thereaction mixture was concentrated under high vacuum and triturated byacetone (3×10 mL) to give Intermediate 139,(S)—N-methyl-1-(piperidin-4-yl)pyrrolidine-2-carboxamide dhydrochloride(0.135 g, 67.16%) as a colourless solid. The data for the title compoundare in Table 2.

Route 9 General Procedure for the Preparation of Piperidines Carrying aN-linked Cyclic Amine at the 4-Position Via Reductive Alkylation andDeprotection as Exemplified by the Preparation of Intermediate 181,4-[2-(1H-pyrazol-1-yl)pyrrolidin-1-yl]piperidine Trifluoroacetate Salt

5-(Pyrrolidin-2-yl)-1H-pyrazole dihydrochloride (0.105 g, 0.50 mmol) wasdissolved in DMF (5 mL). To the solution was added DIPEA (0.435 mL, 2.5mmol), ACOH (0.043 mL, 0.75 mmol), tert-butyl4-oxopiperidine-1-carboxylate (0.100 g, 0.50 mmol) and STAB (0.318 g,1.50 mmol) in that order. The mixture was stirred at it for 2 days, thenconcentrated to remove DMF. The residue was partitioned between sat.aqueous NaHCO₃ and DCM (×2) and the organic phase was passed through aphase separator and concentrated to give the crude tert-butyl4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (0.271g, >100%) as an ol.

LCMS (Method C): m/z 321 (M+H)⁺ (ES), at 1.18 min, UV active

A solution of the crude tert-butyl4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (0.271 g,assumed 0.50 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at RT for110 min then diluted with toluene and concentrated. The residue wasazeotroped with toluene to give the crude Intermediate 181,4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidine trifluoroacetate salt(0.598 g, >100%) as an oil. Used immediately. The data for the titlecompound are in Table 2.

Route 10 General Procedure for the Preparation of Pyrrolidinone orOxadiazolone Containing Piperidines Via Copper Catalyzed Coupling toPyridine Followed by Hydrogenation as Exemplified by the Preparation ofIntermediate 184, 5-methyl-1-(piperidin-4-yl)pyrolidin-2-one AcetateSalt

A mixture of 5-methylpyrrolidin-2-one (0.050 g, 0.50 mmol),4-iodopyridine (0.103 g, 0.50 mmol),(trans)-N,N′-dimethylcyclohexane-1,2-diamine (0016 mL, 0.10 mmol), CuI(0.019 g, 0.10 mmol) and K₂CO₃ (0.209 g, 1.5 mmol) in dioxane (2 mL) wassealed in a nitrogen flushed glass tube and heated with stirring at 150°C. overnight. The cooled reaction mixture was concentrated onto flashsilica (5 mL). The resulting powder was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63μm, 60 Å], 30 ml per min. 0 to 5% Solvent A in DCM, where Solvent A is10% of (7 M NH/MeOH) in MeOH) to give5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (0.088 g, 99%) as an oil.

LCMS (Method C): m/z 177 (M+H)⁺ (ES⁺), at 0.69 min, UV active

The 5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (0.080 g, 0.45 mmol) wasdissolved in AcOH (8 mL) and hydrogenated over 10% Pt/C catalyst at 80bar pressure and 100° C. at a flow-rate of 1 mL/min using a H-Cube. Thesolution was then concentrated and the residue azotroped with toluene(×2) to afford the crude Intermediate 184,5-methy-1-(piperidin-4-yl)pyrrolidin-2-one acetate salt (0.186 g, >100%)as an oil. The data for the title compound are in Table 2.

Route 11 Typical Procedure for the Preparation of Piperidines Via CopperCatalyzed Coupling to Pyridine Followed by Hydrogenation as Exemplifiedby the Preparation of Intermediate 199,(5R)-6-methyl-1-(piperidin-4-yl)pyrrolidin-2-one Acetate Salt andIntermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl)pyrrolidin-2-oneAcetate Salt

Intermediate 199, (5R)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-oneAcetate Salt

To a solution of (58)-5-(hydroxymethyl)pyrrolidin-2-one (2.0 g, 17 mmol)and 4-methylbenzenesulfonyl chloride (5.3 g, 28 mmol) in DCM (24 mL) wasadded triethylamine (12 mL, 88 mmol). The resulting mixture was stirredat RT overnight then concentrated. The residue was dissolved in DCM andwashed with 1 M aqueous HCl (×3) and brine (×1), then passed through aphase separator and concentrated to give a brown solid. The solid wasrecrystallized from DCM/isohexane to give a tan solid that was removedby filtration, washed with DCM/isohexane mixture and dried in air togive [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate (3.13 g,87%).

LCMS (Method C): m/z 270 (M+H)⁺ (ES), at 0.97 min, UV active

A mixture of [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate(0.50 g, 1.9 mmol) and lithium bromide (0.484 g, 5.6 mmol) in acetone (5mL) was heated at reflux under N₂ overnight, then allowed to cool. Thesolvent was removed by concentration, the residue was distributedbetween DCM and H₂O and the phases were separated. The aqueous phase wasextracted with DCM (×3), then the organic phases were passed through aphase separator and concentrated to give(5S)-5-(bromomethyl)pyrrolidin-2-one (0.284 g, 88%) as a gum.

LCMS (Method C): m/z 178/180 (M+H)⁺ (ES⁺), at 0.37 min, weakly UV active

A solution of (58)-5-(bromomethyl)pyrrolidin-2-one (0284 g, 1.8 mmol) intriethylamine (0.287 mL, 1.9 mmol) and ethanol (32 mL) was hydrogenatedover 10% Pd/C catalyst at 50 bar pressure and at RT at a flow-rate of 1mL/min using a H-Cube. The solution was concentrated to give the crude(5R)-5-methylpyrrolidin-2-one (0.445 g, >100%) as a sticky solid.

LCMS (Method C): m/z 100 (M+H)⁺ (ES⁺), at 0.34 min, weakly UV active

The crude (5R)-5-methylpyrrolidin-2-one (0.445 g, assumed 1.5 mmol) wasreacted according to Route 10 (coupling with Intermediate 183) to givethe crude Intermediate 199,(5R)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-one acetate salt (0.125 g,46%) as an oil. The data for the title compound are in Table 2.

Intermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl)pyrrolidin-2-oneAcetate Salt

Methyllithium (1.5 M in other, 7.4 mL, 11 mmol was added quickly withstirring to a suspension of copper iodide (1.06 g, 5.6 mmol) in THF (6mL), pre-cooled in ice-water under N₂. The pale brown solution wasstirred in ice-water for 45 min, then cooled to −20° C. A solution of[(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.9mmol) in THF (6 ml) was added portion-wise over 2 min and the resultingsolution was stirred at −20° C. for 45 min then in Ice-water overnight,allowing the cooling bath to slowly expire. The mixture was quenchedwith saturated aqueous NH₄Cl (15 mL) and stirred for several hours. Thetwo-phase mixture was extracted with ether (×3), the organic phases werewashed with brine, passed through a phase separator and concentrated togive the crude (5R)-5-ethylpyrrolidin-2-one (0.124 g, 59%) as an oil.

LCMS (Method C): m/z 114 (M+H)⁺ (ES⁺), at 0.50 min, weakly UV active

The crude (5R)-5-ethylpyrrolidin-2-one (0.124 g, 1.10 mmol) was reactedaccording to Route 10 (coupling with Intermediate 183) to give the crudeIntermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl)pyrrolidin-2-oneacetate salt (0.156 g, 72%) as a gum. The data for the title compoundare in Table 2.

Route 12 Typical Procedure for the Preparation of Piperidines ViaCarbamate Formation, Copper Catalyzed Coupling to Pyridine Followed byHydrogenation as Exemplified by the Preparation of Intermediate 206,(4R)-4-methyl-3-(piperidin-4-yl)-1,3-oxazolidin-2-one Acetate Salt

A solution of triphosgene (0.297 g, 1.0 mmol) in DCM (5 mL) was addedportion-wise over 1 h to a solution of (2R)-2-aminopropan-1-ol (0.156ml, 2.0 mmol) and triethylamine (0.56 mL, 4.0 mmol) In DCM (5 mL),precooled in ice-water. The mixture was stirred in ice-water for afurther 2 h, then ether (6 mL) was added. The thick suspension wasfiltered through a sinter, washing the solid with more ether (6 mL). Thefiltrate was concentrated onto flash silica (5 mL) and the resultingpowder was purified by column chromatography (normal phase, [BiotageSNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å], 30 mL per min, 100% EtOAc)to give (4R)-4-methyl-1,3-oxazolidin-2-one (192 mg, 95%) as a solid.

LCMS (Method C): m/z 102 (M+H)⁺ (ES), at 0.14 min, UV inactive

(4R)-4-Methy-1,3-oxazolidin-2-one (0.188 g, 1.9 mmol) was reactedaccording to Route 10 (coupling with Intermediate 183) to give the crudeIntermediate 205, (4R)-4-methyl-3-(piperidin-4-yl)-1,3-oxazolidin-2-oneacetate sat (0.343 g, 100%) as a solid. The data for the title compoundare in Table 2.

Route 13 Typical Procedure for the Preparation of Piperidines ViaReductive Aminations, as Exemplified by the Preparation of Intermediate159, tert-butyl4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate

D-Proline methyl ester hydrochloride (0.200 g, 1.208 mmol) and1-Boc-4-piperidinone (0.24 g, 1.208 mmol) were dissolved in DMF (2 mL)at rt and diisopropylethylamine (0.209 mL, 1.208 mmol) was added. Thereaction mixture was stirred at rt for 3 h. STAB (0.512 g, 2.416 mmol)was then added and the reaction mixture was stirred overnight undernitrogen at rt. The solvents were removed in vacuo, and residue waspartitioned between H₂O (15 mL) and EtOAc (25 mL), aqueous layer wasextracted with EtOAc (2×25 mL), organic layers were combined, dried averNa₂SO₄ and solvent was removed in vacuo to give tart-butyl4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate.Intermediate 159, as a white solid (393 mg, >99%). The data for thetitle compound are in Table 2

Route 14 Typical Procedure for the Preparation of Piperidines ViaReductive Aminations, as Exemplified by the Preparation of Intermediate271, tert-butyl 3,3-difluoro-1,4′-bipiperidine-1′-carboxylate

3,3-difluoropiperidine. HCl (0.30 g, 1.90 mmol) and 1-Boc-4-piperidinone(0.379 g, 1.90 mmol) were dissolved in DMF (8 ml) at it anddisopropylethylamine (0.246 g, 1.90 mmol) was added. The reactionmixture was stirred at 50° C. under nitrogen for 2 h. The reactionmixture was cooled to rt, glacial acetic acid (0.114 g, 1.90 mmol andSTAB (1.01 g, 4.76 mmol) was then added and the reaction mixture wasstirred overnight at 50° C. under nitrogen. Water (2 ml) was added tothe cooled reaction mixture and the solvents were removed in vacuo. Theresidue was diluted with sat. NaHCO₃ (aq) (10 ml) and extracted with DCM(2×10 ml) The combined organic layers were passed through a BiotagePhase Separator Cartridge to dry and the solvents were removed in vacuo.The residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 25 g 40-83 μm, 60 Å, 25 mL per min,gradient 0% to 10% MeOH/DCM]) to give tert-butyl3,3-difluoro-1,4′-bipiperidine-1′-carboxylate. Intermediate 271, (0.347g, 60%) as an amber oil. The data for the title compound are in Table 2

Route 15 Typical Procedure for the Preparation of Piperidines ViaTetrazole Formation, Followed by Alkylation as Exemplified by thePreparation of Intermediate 195, 4-(1-methyl-1H-tetrazol-5-yl)piperidineHydrochloride Salt

tert-Butyl 4-cyanopiperidine-1-carboxylate (21 g, 10 mmol), sodium azide(1.95 g, 30 mmol) and ammonium chloride (1.6 g, 30 mmol) were dissolvedin DMF (20 m). The reaction mixture was stirred at 100° C. for 24 h,then diluted with water (250 ml) and extracted with EtOAc (3×100 mL).The combined organic layers were dried (Na₂SO₄) and concentrated to givethe crude product, which was purified by column chromatography (Normalphase, Neutral silica gel, 60-120 mesh, 0 to 5% MeoH in DCM) to givetert-butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (1.25 g, 50%) asa solid.

LCMS (Method F): m/z 198 (M−tBu+H)⁺ (ES⁺), at 1.69 min, UV inactive

tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate (1.2 g, 4.7mmol), iodomethane (2.0 g, 14 mmol) and Cs₂CO₃ (9.6 g, 28 mmol) weredissolved in dry DMF (36 mL). The reaction mixture was stirred at 100°C. for 2 h, then diluted with water (250 mL) and extracted with EtOAc(3×100 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated to give the crude product, which was purified by columnchromatography (Normal phase, Neutral silica gel, 60-120 mesh, 0 to 35%EtOAc in hexane and then 45 to 60% EtOAc in hexane to separate the tworegioisomers. The required regioisomer, tert-butyl4-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.160 g, 13%),was the second to elute from the column and was obtained as a solid.

LCMS (Method F): m/z 212 (M−tBu+H)⁺ (ES⁺), at 1.79 min, UV inactive

tert-Butyl 4-(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (0.160g, 0.60 mmol) was dissolved in dioxane (3 mL). HCl in dioxane (4M, 3 mL,12 mmol) was added at 0° C. and the mixture was stirred at roomtemperature for 5 h. The solvent was removed and the mixture wastriturated with diethyl ether (5 mL) to give4-(1-methyl-1H-tetrazol-5-yl)piperidine hydrochloride salt, Intermediate195, (0.130 g, >100%) as solid. The data for the title compound are inTable 2.

Route 16 Typical Procedure for the Preparation of Piperidines ViaReductive Amination, Amide Formation and Boc-deprotection as Exemplifiedby the Preparation of Intermediate 223,(2R)—N-methyl-1,4′-bipiperidine-2-carboxamide

To a solution or R-pipecolinic acid (1 g, 7.75 mmol) and tert-butyl4-oxopiperidine-1-carboxylate (2.31 g, 11.6 mmol) in MeOH (40 mL), 10%Pd on charcoal (1 g, 50% wet) was added and the reaction mixture wasstirred at room temperature under H₂ (1 atm) for 48 h. The reactionmixture was filtered through a celite bed and the filtrate wasevaporated in vacuo. This crude residue was triturated in DCM (50 mL) togive (R)-1′-(tert-butoxycarbonyl)-[1,4′-bipiperidine]-2-carboxylic acid(1.2 g, 50%) as a white solid. This crude residue was used for the nextstep without further purification.

¹H-NMR (400 MHz; CDCl₃) δ: 1.46 (s, 9H), 1.50-1.59 (m, 1H), 1.75-1.91(m, 4H), 1.93-2.05 (m, 2H), 2.10-2.19 (m, 2H), 2.35-2.41 (m, 1H),2.51-2.69 (m, 3H), 3.41-3.49 (m, 1H), 3.55-3.61 (m, 1H), 3.70-3.79 (m,1H), 4.25-4.36 (m, 2H).

To a solution of(R)-1′-(tert-butoxycarbonyl[1,4′-bipiperidine]-2-carboxylic acid (1.0 g,3.20 mmol) and MeNH₂ (2 M in THF, 3.2 mL, 6.41 mmol) in DCM (20 mL),DIPEA (1.75 mL, 9.60 mmol) was added at 0° C. After stirring for 10 min,1-propane phosphonic anhydride [50% solution in ethyl acetate (4.07 mL,6.41 mmol)] was added and stirred at room temperature for 3 h. Aftercompletion, the reaction mixture was quenched with saturated aq NaHCO₃and extracted with DCM (3×30 mL). The organic layers were combined andwashed with brine, dried (Na₂SO₄) and concentrated in vacuo to givetert-butyl (R)-2-(methylcarbamoyl)-[1,4′-bipiperidine]-1′-carboxylate(4, 1 g, 97%) as a colorless gummy liquid. This crude residue was usedfor the next step without further purification.

¹H-NMR (400 MHz, DMSO) δ: 1.46 (s, 9H), 1.61-1.80 (m, 4H), 1.91-2.08 (m,4H), 2.25-2.33 (m, 2H), 2.61-2.71 (m, 4H), 2.82 (d, J=4.8 Hz, 3H),3.32-3.45 (m, 2H), 4.25-4.36 (m, 2H), 6.85 (br.s., 1H).

To a solution of tert-butyl(R)-2-(methylcarbamoyl)-[1,4′-bipiperidine]-1′-carboxylate (700 mg, 2.15mmol) In dioxane (10 mL) HCl in dioxane (4 M, 10 mL) was slowly added at0° C. and stirred at room temperature for 3 h. The reaction mixture wasconcentrated in vacuo. This was basified with aq sat NaHCO₃ (10 mL) andconcentrated. To the crude reaction mass 5% MeOH/DCM (30 mL) was added,stirred for 10 min and filtered. The filtrate was concentrated in vacuoto give Intermediate 223, (R)—N-methyl-[1,4′-bipiperidine]-2-carboxamide(400 mg, 83%) as a brown gummy liquid. The data for the title compoundare in Table 2.

Route 17 Typical Procedure for the Preparation of Iodo Pyrazoles ViaSandmeyer Reaction as Exemplified by the Preparation of Intermediate250, 4-ethyl-5-iodo-1-methyl-1H-pyrazole

1-Ethyl-4-methyl-1H pyrazole amine (0.5 g, 3.932 mmol), was dissolved indi iodo methane (9.0 mL) at 0-5° C. under nitrogen atmosphere followedby the dropwise addition of isoamyl nitrite and the mixture was stirredfor 2 h at 80° C. then 2 h at room temperature. The reaction mixture waspartioned between H₂O (100 mL) and EtOAc (250 mL), the aqueous layer wasfurther extracted with EtOAc (2×250 mL), the combined organic layerswere dried (Na₂SO₄), filtered and the solvent was removed in vacuo. Theresidue was purified by column chromatography (normal phase, neutralsilica gel, 60-120 mesh, 30 to 50% ethyl acetate in hexane) to give4-ethyl-5-iodo-1-methyl-1H-pyrazole Intermediate 250 (0.5 g, 53.23%) asa light yellowish gum. The data for the title compound are in Table 2.

Route 18 Typical Procedure for the Preparation of Activated CarbamatesVia Deprotection, Carbamate Formation Followed by Reductive Amination asExemplified by the Preparation of Intermediate Intermediate 302,tert-butyl (2R)-2-(difluoromethyl)pyrrolidine-1-carboxylate

6-Boc-2-oxo-1-aza-spiro [3.4]octane (4.00 g, 0.017 mol) was dissolved in4M HCl in dioxane (25 mL) and stirred at it under nitrogen overnight.The solvents were removed in vacuo to give an off white solid which wassuspended in DCM (40 mL), reaction mixture was cooled under nitrogen to0° C. Et₃N (3.60 g, 0.038 mol) and 4-nitrophenyl chloroformate (3.787 g,0.0187 mol) were added and the reaction mixture was and stirred at rtovernight. The reaction mixture was quenched with sat. NaHCO₃ (aq) (30mL) and extracted with DCM (3×20 mL). The organic layers were combinedand dried by passing through a Biotage Phase Separator Cartridge and thesolvents were removed in vacuo. The residue was purified by columnchromatography (normal phase. [Biotage SNAP cartridge KP-sil 50 g 40-63μm, 60 Å, 50 mL per min, gradient 0% to 6% MeOH/DCM]) to give4-nitrophenyl 2-oxo-oxaspiro[3.4]octane-6-carboxylate as a yellow solid(1.40 g, 27%).

LCMS (Method C): m/z 291 (M+H)+ (ES+) at 1.167 min

4-nitrophenyl 2-oxo-8-azaspiro[3.4]octane-8-carboxylate (0.700 g, 2.41mmol) was dissolved in DMF (15 mL). 4-(1H-pyrazole-1-yl)piperidine(0.365 g, 2.41 mmol), glacial acetic acid (0.144 g, 2.41 mmol and STAB(1.535 g, 7.24 mmol) were added, the reaction mixture was stirred at 50°C. under nitrogen overnight. Reaction mixture quenched with water (2 mL)and the solvents were removed in vacuo. The residue was partitionedbetween DCM (20 mL) and sat. NaHCO₃ (aq) (20 mL), aqueous layer wasextracted with DCM (2×20 mL), the organic layers were combined and driedby passing through a Biotage Phase Separator Cartridge and the solventswere removed in vacuo. The residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 25 g 40-63 μm, 60 Å, 25 mLper min, gradient 0% to 10% MeOH/DCM]) to give 4-nitrophenyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Intermediate 302, (0.738 g, 72%). The data for the title compound are inTable 2

General Synthetic Procedures for Examples Route a Typical Procedure forthe Preparation of Piperidines Via Sodium TriacetoxyborohydrideReductive Amination as Exemplified by the Preparation of Example 1-1,ethyl2-[4-(1H-imidazol-2-yl)-piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

4-(1H-imidazol-2-yl)piperidine dihydrochloride (1.43 g, 7.1 mmol) andethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (1.60 g, 7.1 mmol) weredissolved in DCM (60 mL) at rt and titanium isopropoxide (2.31 mL, 7.81mmol) was added. The reaction mixture was stirred at rt for 1 h. Thereaction mixture was cooled to −5° C., then STAB (3.01 g, 14.2 mmol) andacetic acid (350 μL, 0.4.26 mmol) were added and the reaction mixturewas stirred overnight under nitrogen while warming to rt. The reactionmixture was quenched with the addition of NaHCO₃ (sat aq.) (10 mL) anddiluted with DCM then filtered through a pad of celite. The layers wereseparated and the aqueous layer was extracted with DCM. The combined DCMlayers were washed with brine, then dried over MgSO₄. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase. [Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 80 Å, 50mL per min, gradient 1% to 10% MeOH in DCM with 0.5% NEt₃] to give aninseparable mixture of diastereomers of ethyl2-[4-(1H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate(2.45 g, 98.3%) as a white solid. Preparative HPLC was used to separatethe diastereomers, using a Phenomenex Gemini-N C18 column, 150×21 mm,eluting with 28 to 38% MeCNH₂O at 18 mL/min and collecting fractions bymonitoring at 218 nm to give isomer 1 ethyl2-[4-(1H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate(0.338 g, 14%) as a colourless solid and isomer 2 ethyl2-[4-(1H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate(0.389 g, 18%) as a colourless solid. The data for Isomer 2 are in Table3.

Route b Typical Procedure for the Preparation of Piperidines Via SodiumCyanoborohydride and Zinc Chloride Reductive Amination as Exemplified bythe Preparation of Example 1-3, Ethyl2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

4-(4-(Trifluoromethyl)-1H-imidazol-2-yl)piperidine (100 mg, 0.46 mmol),ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (89 mg, 0.46 mmol),ZnCl₂ (2 mg, 0.01 mmol) and triethylamine (0.3 mL, 2.28 mmol) weredissolved in MeOH (5 mL) and the reaction mixture was stirred at 50° C.for 2 h. The reaction mixture was cooled down to 0° C., and NaBH₂CN (114mg, 1.83 mmol) was added portion wise. The resulting reaction mixturewas stirred at 25° C. for 7 h and the solvents were removed in vacuo.The residue was partitioned between H₂O (50 mL) and EtOAc (35 ml), theaqueous layer was extracted with EtOAc (2×35 mL), the organic layerswere combined, dried (Na₂SO₄) and the solvent was removed in vacuo. Theresidue was purified by Prep HPLC [reverse phase (X-BRIDGE, C-18, 250×19mm, 5 um, 18 mL per min, gradient 28.0% (over 40.0 mins), 100% (over 3.0mins) then 28.0% (over 5.0 min), 0.1% NH₃ in MeCN/water] to give ethyl2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 1-3 Isomer 1, (15 mg, 8.24%) as a yellow solid and ethyl2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 1-3 isomer 2, (12 mg, 5.6%) as a yellow solid. The data forIsomer 2 are in Table 3

Route c Typical Procedure for the Conversion of TrifluoromethylSubstituted Imidazoles to Cyano Substituted Imidazoles as Exemplified bythe Preparation of Example 1-4, Ethyl2-[4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

Ethyl2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(200 mg, 0.50 mmol) was dissolved in NH₃ solution (20 mL) and stirred at60° C. for 8 h. The solvents were removed in vacuo and the residue waspartitioned between H₂O (60 mL) and EtOAc (40 mL), aqueous layer wasextracted with EtOAc (2×40 mL), organic layers were combined, dried(Na₂SO₄). The solvent was removed in vacuo and the residue was purifiedby Prep HPLC [reverse phase (DURASHELL, C-18, 250×21.2 mm, 5 um, 22 mLper min, gradient 25.0% (over 30.0 mins), 100% (over 3.0 mins) then25.0% (over 7.0 min), 0.1% NH3 in MeCN/water] to give ethyl2-(4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,Example 1-4 Isomer 1, (26 mg, 14.6%) as a yellow solid and ethyl2-[4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-4 Isomer 2, (25 mg, 14.06%) as a yellow sold. The data forIsomer 2 are in Table 3.

Route d Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination, Boc-Deprotection andEthylcarbamate Formation as Exemplified by the Preparation of Example1-7, Ethyl2-[4-(1-methyl-H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

4-(1-Methylimidazol-2-yl)piperidine hydrochloride (0.244 g, 1.21 mmol)and 6-Boc-2-oxo-6-azaspiro[3.4]octane (0.273 g, 1.21 mmol) weredissolved in DCM (10 mL) at rt and titanium isopropoxide (0.4 mL, 2.42mmol) was added. The reaction mixture was stirred at rt for 1 h. Thereaction mixture was cooled to −5° C., then STAB (0.513 g, 2.42 mmol)and acetic acid (27 μL, 480 μmol) were added and the reaction mixturewas stirred overnight under nitrogen while warming to rt. The reactionmixture was quenched with the addition of NaHCO₃ (sat aq.) (10 mL) anddiluted with DCM then filtered through a pad of celite. The layers wereseparated and the aqueous layer was extracted with DCM. The combined DCMlayers were washed with brine, then dried over MgSO₄. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase. [Biotage SNAP cartridge KP-sil 25 g, 40-83 μm, 60 Å, 50mL per min, gradient 1% to 10% MeOH in DCM]) to give an inseparablemixture of Isomers of tert-butyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidine]-8-azaspiro[3.4]octane-6-carboxylate(0.330 g, 72%) as a yellow gum.

LCMS (Method A): m/z 374 (M+H)⁺ (ES), at 1.68 min, UV inactive.

Tert-butyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidine]-8-azaspiro[3.4]octane-8-carboxylate(0.326 g, 0.87 mmol) was dissolved in 4 M hydrogen chloride in dioxane(12 mL, 5.2 mmol). The reaction mixture was stirred at it for 18 h. Thevolatiles were then removed in vacuo and the residue dissolved DCM (17mL) and triethylamine (0.49 mL, 3.49 mmol). Ethyl chloroformate (125 μL,1.31 mmol) was added dropwise and the solution stirred at rt for 18 h.The mixture was then poured into NaHCO₃ (aq) (75 ml) and DCM (75 mL),extracted (2×75 mL), and the combined DCM extracts washed with brine (20mL) then dried over MgSO_(A). After concentration, the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-83 μm, 60 Å, 50 mL per min, gradient 1% to 10% MeOH inDCM]) to provide ethyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylateas a brown oil as a mixture of diastereomers (0.25 g, 83%). PreparativeHPLC was used to separate the diastereomers, using a Phenomenex Gemini-NC18 column, 150×21 mm, eluting with 38 to 48% MeCN/H₂O at 18 m/in andcollecting fractions by monitoring at 218 nm to give ethyl2-[4-(1-methyl-1H-imidazo-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-7 Isomer 1, (0.044 g, 15%) as a colourless oil and ethyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate.Example 1-7 Isomer 2, (0.031 g, 10%) as a colourless oil. The data forIsomer 2 are in Table 3

Route e Typical procedure for the Hydrogenation of Compounds Containing3,6-dihydropyridin-1(2H)-yl to Give Compounds Containing Piperidinyl asExemplified by the Preparation of Example 1-9, Methyl2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

Methyl2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-dihydropyridin-1(2H)-yl)-6-azaspiro[3.4]octane-6-carboxylate(102 mg, 0.29 mmol) [synthesized via route d and intermediates 3 and 34]was dissolved in MeOH (10 mL) and 10% Pd/C (25 mg) was added. Thereaction mixture was purged with H₂ gas then stirred at 25° C. for 20 hunder a balloon of H₂. The reaction mixture was filtered through celiteand wash with MeOH, the solvents from the filtrate were removed invacuo, and the residue was purified by preparative HPLC (X Bridge, C-18,150×30 mm, 5 um, 40 mL per min, gradient 30% (over 12.00 mins), 100%(over 14.00 mins), then 30% (over 14.01 mins). 0.1% Ammonia inAcetonitrile/water] to give methyl2-[4-(1,5-dimethyl-H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-9 Isomer 1, (5.6 mg, 5.8%) as a colourless gum and methyl2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-9 Isomer 2, (11.6 mg, 11.7%) as a colourless gum. The data forIsomer 2 are in Table 3.

Route f Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination, Boc-deprotection andEthylcarbamate Formation as exemplified by the Preparation of Example1-36, Ethyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

4-(1H-1,2,4-Triazol-1-yl)piperidine (0.152 g, 1.0 mmol) and6-Boc-2-oxo-6-azaspiro[3.4]octane (0.222 g, 1.05 mmol) were dissolved inDCM (10 mL) under N₂ at rt and acetic acid (0.13 mL, 2.22 mmol) wasadded. The reaction mixture was stirred at rt for 2 h, STAB (0.53 g,2.50 mmol) added and the reaction mixture stirred overnight at rt. Thereaction mixture was quenched with the addition of NaHCO₃ (sat aq.) (30mL), extracted with DCM (4×25 mL) and the combined DCM layers passedthrough a Biotage phase separator. The solvents were removed in vacuo,to give a crude mixture of diastereomers of tert-butyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylatewhich was used without purification.

LCMS (Method C): m/z 362 (M+H)⁺ (ES⁺), at 1.58 min and 1.61 min, UVinactive.

Crude tert-butyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(assumed 1.0 mmol) was dissolved in 4 M hydrogen chloride in dioxane(1.2 mL, 5.2 mmol) and the reaction mixture stirred at rt overnight. Thevolatiles were removed in vacuo and the residue dissolved in DCM (10 ml)and NEt₃ (0.70 mL, 5.0 mmol) added. Ethyl chloroformate (0.14 mL, 1.5mmol) was added dropwise and the solution stirred at rt overnight. Themixture was poured into NaHCO₃ (aq) (40 mL) extracted with DCM (4×40mL), and the combined DCM layers passed through a Biotage phaseseparator. The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 40 mL per min, gradient 0% to 10% MeOH inDCM) to give an inseparable mixture of diasteromers of ethyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Preparative HPLC was used to separate the diastereomers, using aPhenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with25 to 55% MeCN/Solvent B over 14.4 at 30 mL/min [where Solvent B is 0.2%of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 210nm to give ethyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-36 Isomer 1, (0.026 g, 8%) as a colourless solid and ethyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Example 1-6 Isomer 2, (0.028 g, 8%) as a colourless solid. The data forIsomer 2 are in Table 3.

Route g Typical Procedure for the Alkylation of Imidazole ContainingCompounds Using Sodium Hydride in DMF as Exemplified by the Preparationof Example 1-51, Ethyl2-{4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Mixture of diastereomers of ethyl2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(150 ng, 0.45 mmol) was dissolved in anhydrous DMF (3 mL), treated witha 0% suspension of sodium hydride in mineral oil (27 mg, 0.68 mmol) andstirred at RT for 2 h. 2-Bromoethyl methyl ether (0.051 mL, 0.54 mmol)was added and the mixture was stirred at RT overnight. The mixture wasconcentrated to remove DMF. The residue was dissolved in MeOH andconcentrated onto flash silica (5 mL). The resulting powder was purifiedby column chromatography (normal phase, [Biotage SNAP cartridge KP-sil25 g, 40-63 μm, 60 Å], 30 mL per min. 0 to 20% Solvent A in DCM, whereSolvent A is 10% of (7 M NH3/MeOH) in MeOH) to give a mixture ofdiastereomers of ethyl2-(4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylate(159 mg, 90%). This mixture was dissolved in MeOH and the solution waspurified by preparative reversed phase HPLC using a Phenomenex Gemini-NX5 μm C18 110A Axia column, 100×30 mm, eluted with 15 to 45% MeCN/SolventB over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O)in H₂O] and collecting fractions by monitoring at 210 nm to give ethyl2-{4-[1-(2-methoxyethyl)-1H-Imidazo-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 1-61 Isomer 1, (54 mg, 31%) and ethyl2-{4-[1-(2-methoxyethyl)-1H-4-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 1-61 Isomer 2, (27 mg, 15%).

The data for Isomer 2 are in Table 3

Route h Typical Procedure for the Alkylation of Imidazole ContainingCompounds Using Potassium Carbonate in DMF as Exemplified by thePreparation of Example 1-62, Ethyl2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Mixture of diastereomers of ethyl2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(150 mg, 0.45 mmol) was dissolved in anhydrous DMF (3 mL). Potassiumcarbonate (187 mg, 1.4 mmol) and bromoacetonitrile (0.114 mL, 1.6 mmol)were added and the mixture was stirred at RT over two nights. Themixture was concentrated to remove DMF. The residue was dissolved inMeOH and concentrated onto flash silica (5 mL). The resulting powder waspurified by column chromatography (normal phase. [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å], 30 mL per min, 0 to 20% Solvent A in DCM,where Solvent A is 10% of (7 M NH3/MeOH) In MeOH) to give a mixture ofdiastereomers of ethyl2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(91 mg, 54%). This mixture was dissolved in MeOH and the solution waspurified by preparative reversed phase HPLC using a Phenomenex Gemini-NX5 μm C18 110A Axia column, 100×30 mm, eluted with 15 to 45% MeCN/SolventB over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₂/H₂O)in H₂O] and collecting fractions by monitoring at 210 nm to give ethyl2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 1-52 Isomer 1, (8 mg, 5%) and ethyl2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 1-62 Isomer 2, (5 mg, 3%). The data for Isomer 2 are in Table 3

Route i Procedure for the Preparation of Example 1-63,(2-(1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl)-1H-imidazol-1-yl)aceticAcid and Example 1-64, ethyl2-(4-(1-[2-(methylamino)-2-oxoethyl]-1H-4-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

Mixture of diastereomers of ethyl2-[4-(1H-Imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(500 mg, 1.5 mmol) was reacted with 60% dispersion of sodium hydride inmineral oil (90 mg, 2.3 mmol) and methyl bromoacetate (0.171 mL, 1.8mmol) in DMF (10 mL) using the method of Route g to give a mixture ofdiastereomers of ethyl2-{4-[1-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(393 mg, 65%).

LCMS (Method C): m/z 405 (M+H)⁺ (ES⁺), at 1.12 & 1.17 min, weakly UVactive.

The mixture of diastereomers of ethyl2-{4-[1-(2-methoxy-2-oxoethyl)-1H-imidazo-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(180 mg, 0.45 mmol) was stirred with lithium hydroxide monohydrate (75mg, 1.8 mmol) In THF (4 mL) and H₂O (1 mL) at rt for 5 days. The mixturewas concentrated to remove THF, acidified with 1M aqueous HCl andconcentrated to afford the crude mixture of diastereomers of(2-(1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl-1H-imidazol-1-yl)aceticacid (0.4 g, >100%). Approximately 0.2 g of this mixture was dissolvedin MeOH and the solution was purified by preparative reversed phase HPLCusing a Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm,eluted with 5 to 15% MeCN/Solvent B over 14.4 min at 30 mL/min [wheresolvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions bymonitoring at 210 nm to give(2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)aceticacid, Example 1-53 Isomer 1, (30 mg, 17%) and(2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)aceticacid, Example 1-63 Isomer 2, (22 mg, 13%).

The data for Isomer 2 are in Table 3.

The remaining crude mixture of diastereomers of(2-{1-[6-(ethoxycarbonyl-8-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)aceticacid. Example 1-3, (0.2 g, assumed 0.22 mmol) was dissolved in DMF (3mL) and treated with diisopropylethylamine (0.155 mL, 0.89 mmol) and asolution of methylamine in methanol (2M, 0.33 mL, 0.86 mmol. HATU (0.127g, 0.33 mmol) was then added and the mixture was stirred at RTovernight. The mixture was concentrated to remove DMF, the residue wasdissolved in a mixture of DCM and MeOH and concentrated onto flashsilica (10 mL). The resulting powder was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63μm, 60 Å], 30 mL per min 0 to 20% Solvent A in DCM, where Solvent A is10% of (7 M NH3/MeOH) in MeOH) to give a mixture of diastereomers ofethyl2-(4-[1-[2-(methylamino)-2-oxoethyl]-1H-imidazol-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate.This mixture was dissolved in MeOH and the solution was purified bypreparative reversed phase HPLC using a Phenomenex Gemini-NX 5 μm C18110A Axia column, 100×30 mm, eluted with 15 to 45% MeCN/Solvent B over14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O]and collecting fractions by monitoring at 210 nm to give ethyl2-(4-{1-[2-(methylamino)-2-oxoethyl-1H-imidazol-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-carboxylate,Example 1-64 Isomer 1, (9 mg, 4%) and ethyl2-(4-(1-{2-(methylamino)-2-oxoethyl]-1H-imidazo-2-yl)piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 1-4 Isomer 2, (6 mg, 3%). The data for Isomer 2 are in Table 3

Route j Typical Procedure for the Preparation of Piperidines ViaCarbamate Formation, as Exemplified by the Preparation of Example 1-70,Ethyl2-{4-[(2R)-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

4-nitrophenyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(0.125 g, 0.294 mmol) was suspended in anhydrous THF (4 mL) andsonicated to cause dissolution. Sodium hydride, 0.0% dispersion inmineral oil. (0.026 g, 0.647 mmol) was added and the reaction mixturewas stirred at rt under nitrogen for 10 mins. Ethanol-1,1-2,2,2-d5(0.150 g, 2.94 mmol) was added and the reaction mixture was stirred atrt under nitrogen overnight. Water (1 mL) was added to the reactionmixture and the solvents were removed in vacuo. The residue waspartitioned between DCM (20 mL) and sat. NaHCO₃ (aq) (10 mL), aqueouslayer was extracted with DCM (2×10 mL). The organic layers were combinedand dried by passing through a Biotage Phase Separator Cartridge. Thesolvents were removed in vacuo, and the residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g 40-63Lm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH/DCM]). The residue wasfurther purified by preparative reversed phase HPLC (PhenomenexGemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with 20 to 50%MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is 0.2% of(28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at 210 nm)to give (²H₅)ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-70 Isomer 1, (0.017 g, 17%) as a white solid and (²H₅)ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 1-70 Isomer 2, (0.013 g, 13%) as a white solid. The data forIsomer 2 are in Table 3.

Route k Typical Procedure for the Preparation of Piperidines ViaFormamide Formation as Exemplified by the Preparation of Example 2-2,Ethyl2-[4-formylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

A mixture of formic acid (2 mL) and acetic anhydride (0.1 mL, 1.43 mmol)were stirred at 60° C. for 1 h, then the reaction was cooled to 0° C.,and a mixture of diastereomers of ethyl2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate.HCl(100 mg, 0.30 mmol) In THF (2 ml) was added dropwise. The resultingreaction mixture was stirred at 60° C. for 8 h, adjusted to basic pHthen the reaction mixture was partitioned between H₂O (40 mL) and EtOAc(25 mL) The aqueous layer was further extracted with EtOAc (2×25 ml) andthe organic layers were combined and dried over Na₂SO₄. Solvents wereremoved in vacuo and the residue was purified by preparative HPLC (XBridge, C-15, 150×30 mm, 5 um, 40 mL per min, gradient 30% (over 12.00mins), 100% (over 14.00 mins), then 30% (over 14.01 mins), 0.1% Ammoniain Acetonitrile/water] to give ethyl2-[4-(1-formylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 2-2 isomer 1 (14.8 mg, 13.0%) as a yellow gum and ethyl2-[4-(1-formylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 2-2 isomer 2 (12.5 mg, 11.1%) as a yellow gum. The data forIsomer 2 are in Table 3

Route L Typical Procedure for the Preparation of Piperidines Via AmideFormation as Exemplified by the Preparation of Example 2-4, Ethyl2-{4-[1-(trifluoroacetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Ethyl2-(4-(pyrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(50 mg, 0.15 mmol) and NEt₃ (0.06 mL, 0.45 mmol were dissolved in THF (3mL) at rt. Ethyl 2,2,2-trifluoroacetate (0.03 mg, 022 mmol) was addeddropwise, and the resulting reaction mixture was stirred at it for 8 h.The reaction mixture was partitioned between H₂O (40 mL) and EtOAc (25mL), the aqueous layer was further extracted with EtOAc (2×25 mL), theorganic layers were combined and dried over Na₂SO₄. Solvents wereremoved in vacuo and residue was purified by preparative HPLC (X Bridge,C-18, 150×30 mm, 5 um, 40 mL per min, gradient 30% (over 12.00 mins),100% (over 14.00 mins), then 30% (over 14.01 mins), 0.1% Ammonia inAcetonitrile/water] to give ethyl2-{4-[1-(trifluoroacetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateExample 2-4 isomer-1 (5.5 mg, 8.0%) as a yellow gum and ethyl2-(4-[1-(trifluoroacetyl)pyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,Example 2-4 isomer-2 (6.2 mg, 9.7%) as a yellow gum. The data for Isomer2 are in Table 3

Route m Typical Procedure for the Preparation of Piperidines ViaAmide/Carbamate/Urea Formation as Exemplified by the Preparation ofExample 2-17, ethyl2-(4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(2.10 g, 5.65 mmol) was dissolved DCM (20 mL) and triethylamine (1.54mL, 11.1 mmol). Methylaminoformyl chloride (620 mg, 6.63 mmol) was addedand the solution stirred at rt for 2 h. The mixture was then poured into1M NaOH (aq) (50 mL), extracted with DCM (2×50 mL), and the combined DCMextracts washed with brine (50 mL) then passed through a Biotage phaseseparator and concentrated in vacuo, to provide ethyl2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateas a yellow solid and as a mixture of diastereomers (1.79 g, 82%).Preparative HPLC was used to separate the diastereomers, using aPhenomenex Gemini-NX C18 column, 100×30 mm, eluting with 25 to 35%MeCN/0.2% ammonia in H₂O (v) at 18 mL/min and collecting fractions bymonitoring at 210 nm to give Example 2-17 Isomer 1, ethyl2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(0.78 g, 36%) as a colourless oil and Example 2-17 Isomer 2, ethyl2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(0.67 g, 31%) as a colourless oil. The data for Isomer 2 are in Table 3

Route n Typical Procedure for the Preparation of Piperidines ViaUrea/Carbamate Formation as Exemplified by the Preparation of Example2-19, Ethyl2-{4-[1-(ethylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate.HCl(100 mg, 0.30 mmol), diethyl amine (0.3 mL, 0.80 mmol) and NE (0.1 mL,0.90 mmol) were dissolved in DCE (5 mL) at rt. CDI (145 mg, 0.60 mmol)was added and the reaction mixture was stirred at it for 15 h. Thereaction mixture was partitioned between H₂O (40 mL) and EtOAc (25 mL),the aqueous layer was further extracted with EtOAc (2×25 mL), theorganic layers were combined, dried (Na₂SO₄), the solvents were removedin vacuo and residue was purified by Prep HPLC [reverse phase HPLC(X-BRIDGE, C-18, 250×19 mm, 5 um, 15 mL per min, gradient 30.0% to 38.0%(over 25.0 mins), 100.0% (over 3.0 mins) then 30.0% (over 2.0 mins),0.1% NH₃ in MeCN/water] to give ethyl2-(4-(1-(ethylcarbamoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,Example 2 19 isomer-1. (7.5 mg, 6.20%) as a yellow gum and ethyl2-(4-(1-(ethylcarbamoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-8-carboxylate,Example 2-19 isomer 2. (8.1 mg, 6.60%) as a yellow gum. The data forIsomer 2 are in Table 3

Route o Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-22, Ethyl2-[4-(1-methylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate.HCl(200 mg, 0.60 mmol) and formaldehyde (40% soln, 1.01 mL, 3.60 mmol) weredissolved in H₂O (2 mL) at 25° C. Formic acid (0.303 mL, 0.90 mmol) wasadded dropwise and the resulting mixture was stirred at 70° C. for 14 h.The reaction mixture was quenched with NaHCO₃ solution (5 mL), then thereaction mixture was partioned between H₂O (50 mL) and EtOAc (35 mL).The aqueous layer was further extracted with EtOAc (2×35 mL), organiclayers were combined and dried over Na₂SO₄. Solvents were removed invacuo and the residue was purified by Prep HPLC [reverse phase HPLC(X-Bridge, C-18, 250×19.0 mm, 5 um, 14 mL per min, gradient 37% (over28.0 mins), 100% (over 4.0 mins) then 37% (over 3.0 mins), 0.1% NH3 InMeCN/water] to give ethyl2-(4-(1-methylpyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-8-carboxylate,Example 2-22 isomer 1 (12 mg, 6.80%) as a yellow gum and ethyl2-(4-(1-methylpyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,Example 2-22 isomer 2 (11 mg, 5.30%) as a yellow gum. The data forIsomer 2 are in Table 3

Route p Typical Procedure for the Preparation of Piperidines Via AmideFormation as Exemplified by the Preparation of Example 2-23, Ethyl2-{4-[1-(N-methylglycyl)pyrrolidin-2-yl]piperidin-1-yl}-azaspiro[3.4]octane-6-carboxylate

N-[(benzyloxy)carbonyl]-N-methylglycine (73 mg, 0.33 mmol) was dissolvedin acetonitrile (5 mL) followed by addition of HATU (170 mg, 0.45 mmol)and DIPEA (0.2 mL, 0.90 mmol). The reaction mixture was stirred at 0° C.for 10 minutes, followed by addition of a mixture of diastereomers ofethyl2-(4-(pyrrolidin-2-yl)piperidin-1-yl-8-azaspiro[3.4]octane-6-carboxylate.HCl(100 mg, 0.30 mmol) and resulting reaction mixture was stirred at 25° C.for 3 h. The reaction mixture was partitioned between H₂O (50 mL) andEtOAc (35 mL), the aqueous layer was further extracted with EtOAc (2×35mL), the organic layers were combined, dried over Na₂SO₄ and solventswere removed in vacuo. Finally, the residue was purified by columnchromatography (normal basic alumina, activated, 0.5% to 1.0% MeOH inDCM) to give ethyl 2-(4-(1-(N-((benzyloxy)carbonyl)-N-methylglycyl)pyrrolidin-2-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylate (130mg, 80.74%) as a brown gum. Ethyl2-(4-(1-(N-((benzyloxy)carbonyl)-N-methylglycyl)pyrrolidin-2-ylpiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(130 mg, 0.24 mmol) was dissolved in MeOH (10 mL) followed by additionof Pd/C (dry basis, 13 mg). The reaction was then purged with H₂ gas andresulting reaction mixture was stirred at 25° C. for 10 h. The reactionmixture was filtered through a celite plug and washed with methanol,then the filtrate dried over Na₂SO₄ and solvents were removed in vacuo.The residue was purified by Prep HPLC [reverse phase HPLC (X-BRIDGE,C-18, 250×19 mm, 5 um, 15 mL per min. gradient 20.0% to 35.0% (over 30.0mins), 100.0% (over 3.0 mins) then 20.0% (over 2.0 mins), 0.1% NH3 inMeCN/water] to give ethyl2-(4-(1-(methylglycyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-23 Isomer 1. (9.0 mg, 9.27%) as a yellow gum and ethyl2-(4-(1-(ethylcarbamoyl)pyrrolidin-2-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylate,Example 2-23 isomer 2, (8.0 mg, 8.50%) as a yellow gem. The data forIsomer 2 are in Table 3

Route q Typical Procedure for the Preparation of Piperidines Via UreaFormation as Exemplified by the Preparation of Example 2-27, ethyl2-(4-[(2S)-1-azetidin-1-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(100 mg, 0.291 mmol) were dissolved DCM (5 mL) and diisopropylethylamine(0.099 mL, 0.58 mol). Triphosgene (88 mg, 0.291 mmol) was added at 0° C.and the solution warmed to rt and stirred for 1 h. The mixture was thendiluted with DCM (50 mL) and washed with H₂O (70 mL). The aqueous layerwas extracted with DCM (2×50 mL), and the combined DCM extracts driedwith Na₂SO₄ and concentrated in vacuo. The residue was dissolved in DCM(5 mL) and azetidine (0.020 mL, 0.291 mmol) and diisopropylethylamine(0.256 mL, 1.48 mmol) were added. The reaction was stirred at rt for 1h. The mixture was then diluted with DCM (50 mL) and washed with H₂O (70mL). The aqueous layer was extracted with DCM (2×50 mL), and thecombined DCM extracts dried with Na₂SO₄ and concentrated in vacuo, toprovide ethyl2-{4-[(2S)-1-(azetidin-1-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateas a yellow solid and as a mixture of diastereomers. The residue waspurified by Prep HPLC [reverse phase HPLC (CHIRALPAK AD-H, C-18, 250×20mm, 5 um, 18.0 mL per min, gradient 0% to 50% (over 15.0 mins), 0.1%Ammonia in acetonitrile and 0.1% ammonia in H₂O to give ethyl(S)-2-(4-(1-(azetidine-1-carbonyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-27 isomer 1 (20 mg, 16.12%) as a colorless gum, and Example2-27 isomer 2 (20 mg, 16.12%) as a colorless gum. The data for Isomer 2are in Table 3

Route r Typical Procedure for the Preparation of Piperidines Via UreaFormation and Dehydration as Exemplified by the Preparation of Example2-42, ethyl2-(4-{(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateand Example 2-138, ethyl2-{4-[(2S)-1-(8-methyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylate.HCl(164 mg, 0.403 mmol) was dissolved in DCM (2 mL) anddiisopropylethylamine (0.209 ml, 1.21 mmol). Triphosgene (43 mg, 0.145mmol) was added at 0° C. and the solution warmed to rt and stirred for18 h. To this mixture was added tert-butyl carbazate (108 mg, 0.82 mmol)and diisopropylethylamine (0.142 mL, 0.82 mmol) and the reaction wasstirred at rt for 18 h. The mixture was then diluted with DCM (20 mL)and washed with saturated NaHCO₃ (aq) (2×20 mL). The aqueous layers wereextracted with DCM (20 mL), and the combined DCM extracts washed withbrine (50 mL) then passed through a Biotage phase separator andconcentrated in vacuo, to provide ethyl 2-{4-[(2S)-1-(tert-butylcarbazoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateas a yellow oil and as a mixture of diastereomers (192 mg, 97%).

LCMS (Method D): m/z 494 (M+H)⁺ (ES⁺), at 1.83 and 1.87 min, UVinactive.

The crude product was dissolved in 4 M hydrogen chloride in dioxane (2.0mL, 8.0 mmol) and DCM (1 mL). The reaction mixture was stirred at rt for1 h. The volatiles were then removed in vacuo, before the reactionmixture was redissolved in DCM (2 mL) and diisopropylethylamine (0.142mL, 0.82 mmol). Acetyl chloride (0.031 mL, 0.428 mmol) was added at 0°C., and the solution warmed to rt and stirred for 2 h. The volatileswere removed in vacuo and carried through to next step without furtherpurification. The residue was dissolved in toluene (2 mL) anddiisopropylethylamine (0.135 mL, 0.78 mmol) and cooled to 0° C.Phosphorus oxychloride was added (0.182 mL, 1.945 mmol) and reactionstirred at 110° C. for 30 minutes, before the reaction was cooled to rtand quenched with ice water (20 mL). The mixture was then diluted withDCM (20 mL) and washed with 1M NaOH_((aq)) (2×20 mL). The aqueous layerswere extracted with DCM (3×20 mL), and the combined DCM extracts washedwith brine (50 mL) then passed through a Biotage phase separator andconcentrated in vacuo. The residue was purified by preparative HPLC,using a Phenomenex Gemini-NX C18 column, 100×30 mm, eluting with 25 to45% MeCN/0.2% ammonia in H₂O (v/v) at 18 mL/min and collecting fractionsby monitoring at 210 nm to give Example 2-42 Isomer 1, ethyl2-(4-{(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(1.7 mg, 1%) as a colourless oil, Example 2-42 Isomer 2, ethyl2-(4-(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(1.6 mg, 1%) as a colourless oil, Example 2-138 Isomer 1, ethyl2-{4-[(2S)-1-(5-ethyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylate(3.9 mg, 2.5%) as a colourless oil and Example 2-138 Isomer 2, ethyl2-(4-[(2S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)pyrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(3.0 mg, 2%) as a colourless oil. The data for Isomers 2 are in Table 3

Route s Typical Procedure for the Preparation of Piperidines ViaCarbamate Formation as Exemplified by the Preparation of Example 2.47,ethyl2-(4-{(2S)-1-[(2-fluoroethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.15 g, 0.44 mmol) and diisopropylethylamine (0.152 mL, 0.89 mmol) weredissolved in DCM (5 mL), then reaction mixture was cooled to 0° C.2-fluoroethyl chloroformate (0.062 g, 0.492 mmol) was added and theresulting reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was partitioned between H₂O (70 mL) and DCM (50 mL), aqueouslayer was further extracted with DCM (2×50 mL), organic layers werecombined, dried over Na₂SO₄, and solvent was removed in vacuo. Theresidue was purified by Prep HPLC [reverse phase HPLC (CHIRALPAK AD-H,C-18, 250×20 mm, 5 um, 18.0 mL per min, gradient 0% to 35% (over 52mins), 0.1% ammonia in acetonitrile and 0.1% ammonia in Water to giveethyl2-(4-(2S)-1-[(2-fluoroethoxy)carbonyl]pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-47 isomer-1 (17 mg, 8.9%) as a yellow gum, and ethyl2-(4-{(2S)-1-[(2-fluoroethoxy)carbonyl]pyrimidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-47 isomer-2 (19 mg, 10%) as a yellow gum. The data for Isomer2 are in Table 3

Route t Typical Procedure for the Preparation of Piperidines Via AmideFormation as Exemplified by the Preparation of Example 2-62, ethyl2-(4-[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.2 g, 0.541 mmol) and triethylamine (0.152 mL, 1.1 mmol) weredissolved in DCM (5 mL), then reaction mixture was cooled to 0° C. andacetoxy acetyl chloride (0.080 g, 0.591 mmol) was added. The reactionmixture was stirred at room temperature for 2 h. The volatiles wereremoved in vacuo, then the residue was dissolved in acetonitrile (25 mL)and 20% NaOH solution in water (10 mL) and stirred 1 at room temperaturefor 1 h. The reaction mixture was partitioned between H₂O (70 mL) andDCM (50 mL), aqueous layer was further extracted with DCM (2×50 mL), theorganic layers were combined, dried over Na₂SO₄, the solvent was removedunder vacuum and residue was purified by Prep HPLC [reverse phase HPLC(CHIRALPAK AD-H, C-18, 250×20 mm, 5 um, 18.0 mL per min, gradient 0% to30% (over 35.0 mins), 0.1% Ammonia in Acetonitrile and 0.1% Ammonia inWater to give ethyl(S)-2-(4-(1-(2-hydroxyacetyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-82 isomer 1 (8 mg, 8.3%) as a colorless gum, and ethyl(S)-2-(4-(1-(2-hydroxyacetyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-62 isomer 2 (12 mg, 12.24%) as a colorless gum. The data forIsomer 2 are in Table 3

Route u Typical Procedure for the Preparation of Piperidines Via AmideFormation as Exemplified by the Preparation of Example 2-3, Ethyl2-{4-[(2)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

(A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.12 g, 0.36 mmol) and diisopropylethylamine (0.123 mL, 0.71 mmol) weredissolved in DCM (10 mL) followed by the addition of trifluoropropanioicacid (0.045 g, 0.394 mmol). The reaction mixture was cooled to 0° C.,and propyl phosphonic anhydride was added (0.140 g, 0.482 mmol 50% EtOAcsolution) was added and the resulting reaction mixture was stirred at25° C. for 2 h. The reaction mixture was partitioned between H₂O (20 mL)and DCM (50 mL), aqueous layer was further extracted with DCM (2×50 mL),organic layers were combined, dried over Na₂SO₄, and solvent was removedin vacuo. The residue was purified by Prep HPLC [reverse phase HPLC(CHIRALPAK AD-H, C-18, 250×20 mm, 5 um, 18.0 mL per min, gradient 0% to30% (over 27.0 mins), 0.1% Ammonia in Acetonitrile and 0.1% Ammonia inWater to ethyl(S-2-(4-(1-(3,3,3-trifluoropropanoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-63 isomer 1 (9 mg, 6.0%) as a colorless gum, and ethyl(S)-2-(4-(1-(3,3,3-trifluoropropanoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-63 isomer 2 (9 mg, 6.0%) as a colorless gum. The data forIsomer 2 are in Table 3

Route v Typical Procedure for the Preparation of Thioamides Via LawessonReagent as Exemplified by the Preparation of Example 2-68, Ethyl2-{4-[(2S)-1-propanethioylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Ethyl2-{4-[(2S)-1-propanoylpyrrolidin-2-yl}-6-piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(0.341 g, 0.87 mmol) was dissolved in THF (4 mL) followed by theaddition of Lawesson Reagent (0.265 g, 0.65 mmol. The reaction mixturewas stirred at 70° C. for 24 hours. The volatiles were removed in vacuo,and the reaction mixture was partitioned between 1M NaOH_((eq)) (50 mL)and DCM (30 mL), aqueous layer was further extracted with DCM (2×50 mL),organic layers were combined, washed with 5% sodiummetabisulfite_((aq)), dried over Na₂SO₄, and solvents were removed invacuo. The residue was purified by Preparative HPLC, using a PhenomenexGemini-NX C18 column, 100×30 mm, eluting with 25 to 45% MeCN/0.2%ammonia in H₂O (v/v) at 18 mL/min and collecting fractions by monitoringat 210 nm to give Example 2-58 Isomer 1 ethyl2-{4-[(2S)-1-propanethioylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(14.1 mg, 4%) as a yellow oil and Example 2-66 Isomer 2, ethyl2-{4-[(2S)-1-propanethioylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(7.8 mg, 2%) as a yellow oil. The data for Isomer 2 are in Table 3

Route w Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-61, Ethyl2-{4-[(2S)-1-ethylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.100 g, 0.29 mmol) and potassium carbonate (0.123 mg, 0.89 mmol) weredissolved in DMF (5 ml) and the reaction mixture was stirred at 60° C.for 2 hours. Iodoethane was then added (0.049 g, 0.31 mmol and thereaction mixture was stirred at 100° C. for 62 hours. The reactionmixture was partitioned between H₂O (70 mL) and EtOAc (50 mL), aqueouslayer was further extracted with EtOAc (2×50 mL), organic layers werecombined, dried over Na₂SO₄, and solvent was removed in vacuo. Theresidue was purified by Prep HPLC (X Bridge, C-18, 150×19 mm, 5 um, 20mL per min, gradient 35% (over 0.01 mins), 100% (over 25.01 mins), then35% (over 30.00 mins), 0.1% ammonia in acetonitrile/water] to give ethyl(S)-2-(4-(1-ethylpyrrolidin-2-ylpiperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-61 isomer 1 (43 mg, 38.8%) as a colourless gum, and ethyl(S)-2-(4-(1-ethylpyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-61 Isomer 2 (26 mg, 23.1%) as a colourless gum. The data forIsomer 2 are in Table 3

Route x Typical Procedure for the Preparation of Piperidines Via s AmideFormation as Exemplified by the Preparation of Example 2-62, ethyl2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl]pyrrolidin-2-yl)piperidin-1-yl}-azaspiro[3.4]octane-6-carboxylate

To a solution of oxalyl chloride (0.065 mL, 0.768 mmol in DCM (2 mL) at0° C. was added 2-pyridinepropionic acid (106 mg, 0.704 mmol) and DMF (1drop). A mixture of diastereomers of ethyl2-(4-[(2S)-pyrolidin-2-yl]piperidin-1-yl)-azaspiro[3.4]octane-6-carboxylate.HCl(262 mg, 0.640 mmol) was dissolved in DCM (1 mL) anddisopropylethylamine (0.355 mL, 2.049 mmol) and added to the solution,which was stirred at rt for 2 h. The mixture was then poured into 1MNaOH (aq) (50 mL), extracted with DCM (2×50 mL), and the combined DCMextracts washed with brine (50 mL) then passed through a Biotage phaseseparator and concentrated in vacuo, to provide ethyl2-{4-[(2S)-13-(pyridin-2-yl)propanoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateas a black oil and as a mixture of diastereomers (0.245 g, 82%).Preparative HPLC was used to separate the diastereomers, using aPhenomenex Gemini-NX C18 column, 100×30 mm, eluting with 25 to 45%MeCN/0.2% ammonia in H₂O (v/v) at 18 mL/min and collecting fractions bymonitoring at 210 nm to give Example 2-62 Isomer 1. ethyl2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.042 g, 14%) as a colourless oil and Example 2-62 Isomer 2, ethyl2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.030 g, 10%) as a colourless oil. The data for 2 are in Table 3

Route y Typical Procedure for the Preparation of Piperidines Via AmideFormation and CBZ-Deprotection as Exemplified by the Preparation ofExample 2-65, Ethyl2-{4-[(2S)-1-[N-[(benzyloxy)carbonyl]-β-alanyl]pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateand Example 2-66, Ethyl2-{4-[(2S)-1-(β-alanyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Example 2-66

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(100 mg, 0.298 mmol) and DIPEA (0.102 mL, 0.597 mmol) were dissolved inCH₂Cl₂ (5 mL cooled to 0° C. and Z-β-ala-OH (0.066 g, 0.298 mmol) addedfollowed by propane phosphonic anhydride (0.123 g, 0.388 mmol, 50% Inethyl acetate). The resulting reaction mixture was stirred at 25° C. for3 h, partitioned between H₂O (70 mL) and CH₂Cl₂ (50 ml) and the aqueouslayer further extracted with CH₂Cl₂ (2×50 mL). The combined organiclayers were dried (Na₂SO₄), filtered and the solvent removed in vacuo togive ethyl2-{4-[(2S)-1-(N-[(benzyloxy)carbonyl]-β-alanyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(100 mg, 71.4%) as a colorless gum which was used directly withoutpurification for the synthesis of Example 2-66.

LCMS (Method I): m/z 541 (M+H)⁺ (ES+) at 4.38 and 4.51 min, UV inactive.

The residue could be purified by Prep HPLC [reverse phase HPLC(CHIRALPAK AD-H, C-18, 250×20 mm, 5 um, 18.0 mL per min, gradient 0% to50% (over 15.0 mins), 0.1% ammonia in acetonitrile and 0.1% ammonia inwater to give ethyl2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateExample 2-65 Isomer 1 (20 mg, 12.5%) as a colourless gum, and ethyl2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateExample 2-6 Isomer 2 (20 mg, 12.5%) as a colourless gum. The data forIsomer 2 are in Table 3.

A mixture of diastereoisomers of ethyl2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(100 mg, 0.185 mmol) was dissolved in TFA (2.0 mL). The resultingsolution was stirred at 80° C. for 3 h, concentrated in vacuo and theresidue purified by Prep HPLC [reverse phase HPLC (CHIRALPAK AD-H, C-18,250×19 mm, 5 um, 13.0 mL per min, gradient 0% to 30% (over 30.0 mins),0.1% ammonia in acetonitrile and 0.1% ammonia in water to give ethyl(S)-2-(4-(1-(3-aminopropanoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-66 Isomer 1 (2 mg, 2.63%) as a colorless gum and ethyl(S)-2-(4-(1-(3-aminopropanoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-66 Isomer 2 (3 mg, 4.0%) as a colorless gum. The data forIsomer 2 are in Table 3

Route z Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-66, Ethyl2-{4-[(2S)-1-(2-fluoroethyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateHCl (100 mg, 0.27 mmol) was dissolved in MeCN (5 mL). CS₂CO₃ (290 mg,0.89 mmol) was added followed by the addition of 2-iodo-1-fluoroethane(56 mg g, 0.32 mmol) and the reaction mixture was stirred at 50° C. for16 h. The reaction mixture was partitioned between H₂O (70 ml) and ethylacetate (50 mL), the aqueous layer was further extracted with ethylacetate (2×50 mL), the organic layers were combined, dried (Na₂SO₄),filtered and the solvent was removed in vacuo. The residue was purifiedby prep HPLC [reverse phase HPLC (CHIRALPAK AD-H, C-18, 250×19 mm, 5 um,15.0 mL per min, gradient 0% to 40% (over 19.0 mins), 0.1% ammonia inacetonitrile and 0.1% ammonia in water] to give ethyl(S)-2-(4-(1-(2-fluoroethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-68 Isomer 1 (25 mg, 25%) as a yellowish gum and ethyl(S)-2-(4-(1-(2-fluoroethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-68 Isomer 2 (20 mg, 20.3%) as a yellowish gum. The data forIsomer 2 are in Table 3.

Route aa Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-69, Ethyl2-{4-[(2S)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]piperidin-1-yl}-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.100 g, 0.29 mmol) and DIPEA (0.112 g, 0.87 mmol) were dissolved inTHF (5 mL) and stirred at 0° C. for 2 hrs. 2,2,2-Trifluoroethyltrifluoromethanesulfonate (0.067 g, 0.29 mmol) was added dropwise at 0°C. and the resulting reaction mixture was stirred at room temperaturefor 24 h. The reaction mixture was partitioned between H₂O (70 mL) andEtOAc (50 mL), the aqueous layer was further extracted with EtOAc (2×50mL), the organic layers were combined, dried (Na₂SO₄ filtered andconcentrated in vacuo. The residue was purified by prep HPLC (X Bridge,C-18, 250×19 mm, 5 um, 12 mL per min, gradient 45% (over 0.01 mins),100% (over 30.00 mins), then 45% (over 32.00 mins), 0.1% ammonia inacetonitrile/water to give ethyl(S)-2-(4-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-69 Isomer 1 (0.003 g, 2.4%) as a colorless gum and ethyl(S)-2-(4-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-69 Isomer 2 (0.002 mg, 1.6%) as a colorless gum. The data forIsomer 2 are in Table 3.

Route ab Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-70, Ethyl2-{4-[(2S)-1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.100 g, 0.20 mmol) and K₂CO₃ (0.123 g, 0.89 mmol) were dissolved inMeCN (5 ml) and reaction mixture was stirred at 80° C. for 2 hrs.1,1,1-Trifluoro-3-iodopropane (0.066 g, 0.29 mmol) was added dropwise at0° C. and the resulting mixture was stirred at room temperature for 8 h.The reaction mixture was partitioned between H₂O (70 mL) and EtOAc (50mL), the aqueous layer was further extracted with EtOAc (2×50 mL), theorganic layers were combined, dried (Na₂SO₄), filtered and the solventwas removed in vacuo. The residue was purified by prep HPLC (X Bridge,C-18, 250×19 mm, 5 um, 15 mL per min, gradient 60% (over 0.01 mins),100% (over 14.01 mins), then 60% (over 23.00 mins), 0.1% ammonia inacetonitrile/water to give ethyl(S)-2-(4-(1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-70 Isomer 1 (0.005 g, 3.9%) as a colorless gum, and ethyl(S)-2-(4-(1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylateExample 2-70 Isomer 2 (0.005 mg, 3.9%) as a colorless gum. The data forIsomer 1 and Isomer 2 are in Table 3

Route ac Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-72, Ethyl(S)-2-(4-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.100 g, 0.29 mmol) and DIPEA (0.14 mL, 0.87 mmol) were dissolved inMeCN (5 mL) and reaction mixture was stirred at RT for 1 h. Methylbromoacetate (0.044 g, 0.29 mmol) was added dropwise and the resultingreaction mixture was stirred at 100° C. for 3 h. The reaction mixturewas partitioned between H₂O (70 mL) and EtOAc (50 mL), aqueous layer wasfurther extracted with EtOAc (2×50 mL), the organic layers werecombined, dried (Na₂SO₄), filtered and the solvent was removed in vacuo.The residue was purified by prep HPLC (X Bridge, C-18, 250×19 mm, 5 um,15 mL per min. gradient 48% (over 0.01 mins), 100% (over 11.1 mins), 48%(over 48.00 mins), 0.1% ammonia in acetonitrile/water] to give ethyl(S)-2-(4-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-72 Isomer 1 (0.012 g, 9.9%) as a colorless gum, and ethyl(S)-2-(4-(1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-72 Isomer 2 (0.013 mg, 10.7%) as a colorless gum. The data forIsomer 2 are in Table 3.

Route ad Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 2-72, ethyl2-(4{(2S)-1-[2-(dimethylamino)-2-oxoethyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.10 g, 0.29 mmol) and NEt₃ (0.087 g, 0.85 mmol) were dissolved indioxane (5 mL) and the reaction mixture was stirred at 60° C. for 30min. 2-Chloro-N,N-dimethylacetamide (0.036 g, 0.29 mmol) was addeddropwise at 0° C. and the resulting mixture was stirred at roomtemperature for 12 h. The reaction mixture was partitioned between H₂O(70 mL) and EtOAc (50 mL), the aqueous layer was further extracted withEtOAc (2×50 mL), the organic layers were combined, dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by prepHPLC (X Bridge, C-18, 250×19 mm, 5 um, 14 mL per min, gradient 20% (over0.01 mins), 40% (over 36.00 mins), 100% (over 44.00 mins), then 20%(over 52.00 mins), 0.1% ammonia in acetonitrile/water] to give ethyl(S)-2-(4-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-72 Isomer 1 (0.002 g, 1.6%) as a yellow gum and ethyl(S)-2-(4-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 2-72 Isomer 2 (0.002 mg, 1.6%) as a yellow gum. The data forIsomer 2 are in Table 3.

Route ae Typical Procedure for the Preparation of Piperidines ViaReductive Amination, Boc-Deprotection and Urea/Amide Formation asExemplified by the Preparation of Example 2-76, Ethyl2-{4-[2-(methylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

To a solution of ter-buty 1-(piperidin-4-yl)isoindoline-2-carboxylate(135 mg, 0.45 mmol) and ethyl3-oxo-8-azabicyclo[3.2.1]octane-6-carboxylate (88 mg, 0.890 mmol in DCM(5 mL), Ti(O^(i)Pr), (0.40 mL, 1.34 mmol) was added at 0° C. and thereaction mixture was stirred for 1 h. Na(OAc)₃BH (283 mg, 1.34 mmol wasadded portion wise to the reaction mixture and stirred at 0° C. for 2 h.After completion, the reaction mixture was quenched with aq sat NaHCO₃and extracted with DCM (3×30 mL). The organic layers were combined andwashed with brine, dried (Na₂SO₄) and concentrated in vacuo. The residuewas purified by flash column chromatography [normal phase, silica gel(100-200 mesh), gradient 5% to 10% methanol in DCM] to give tert-butyl1-(1-(6-(ethoxycarbonyl-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl)isoindoline-2-carboxylate(35 mg, 75%) as a colourless liquid.

MS (ESI +ve): 484

To a solution of tert-butyl1-(1-(6-(ethoxycarbonyl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl)isoindoline-2-carboxylate(290 mg, 0.61 mmol) In 1,4-dioxane (10 mL), HCl in dioxane (4 M, 5 mL)was slowly added at 0° C. and the mixture was stirred at roomtemperature for 5 h. The solvent was evaporated in vacuo. The solidresidue was triturated with diethyl ether to give ethyl2-(4-(isoindolin-1-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylatehydrochloride (250 mg, cr) as an off white solid.

MS (ESI +ve): 384

¹H-NMR (400 MHz; DMSO-d₆) δ: 1.15 (t, J=6.9 Hz, 3H), 1.16-1.26 (m, 1H),1.70-1.90 (m, 5H), 1.95-2.28 (m, 5H), 3.49-3.72 (m, 4H), 3.80-3.72 (m,4H), 3.98-4.15 (m, 2H), 4.13 (q, J=6.9 Hz, 2H), 4.45-4.59 (m, 2H),7.37-7.49 (m, 5H), 9.54, 10.19 (2 br.s., 2H).

To a solution of ethyl2-(4-(isoindolin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylatehydrochloride (240 mg, 0.40 mmol in DCM (5 mL), DIPEA (0.43 mL, 2.38mmol) was added at 0° C. To this reaction mixture methylcarbamicchloride (87 mg, 0.72 mmol) was added and stirred at room temperaturefor 16 h. The reaction mixture was quenched with water (10 mL) and theaq layer was extracted with DCM (2×20 mL). The organic layers werecombined, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified by flash column chromatography [normal phase, silica gel(100-200 mesh), gradient 5% to 10% methanol in DCM] to give ethyl2-(4-(2-(methylcarbamoyl)-isoindolin-1-yl)piperidin-1-yl-6-azaspiro[3.4]octane-6-carboxylateas a mixture of diastereomers (130 mg, 48%) as a gummy liquid.

LCMS (Method M): m/z 441 (M+H)⁺ (ES+), at 1.97 and 1.99 min, UV active.

¹H-NMR (400 MHz; DMSO-d₆): δ: 1.15 (t, J=6.9 Hz, 3H), 1.16-1.26 (m, 4H),1.49-1.90 (m, 5H), 1.91-2.01 (m, 2H), 2.62 (d, J=3.9 Hz, 3H), 2.70-2.90(m, 2H), 3.09-3.25 (m, 4H), 3.97 (q, J=6.8 Hz, 2H), 4.45-4.59 (m, 2H),5.01-5.09 (m, 1H), 6.27 (br.s., 1H), 7.22-7.32 (m, 4H).

Separation of diastereomers using prep HPLC (73.0 mg submitted, GilsonSemi Preparative HPLC system—including Dual Piston Pumps 331 and 332, a171 Diode Array Detector and a GX-271 Liquid Handler, solvents:aqueous=water+0.2% ammonia (28% ammonia solution) andorganic=acetonitrile, gradient: 20-50% organic in aqueous, flow Rate 30ml/min, column Gemini-NX, C18.5μ, 100×30 mm) gave ethyl2-(4-(2-(methylcarbamoyl)-isoindolin-1-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylateExample 2-76 Isomer 1 (8.99 mg, 12.3%) as a colourless gum and ethyl(4-(2-(methylcarbamoyl)-isoindolin-1-yl)piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylateExample 2-76 Isomer 2 (10.9 mg, 14.9%) as a colourless gum. The data forIsomer 1 and Isomer 2 are in Table 3.

Route af Typical Procedure for the Arylation of Pyrrolidine asExemplified by the Preparation of Example 2-77, Ethyl2-{4-[(2S)-1-phenylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylate.HCl(0.100 g, 0.27 mmol) was dissolved in DCM (5 mL), and triethylamine (54ng, 0.54 mmol) was added followed by(1R,5S)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonan-7-one (see J. Luoat al. Tetrahedron Letters 54 (2013), 4505-4508, 58 mg, 0.53 mmol) Thereaction mixture was stirred at room temperature for 16 h, thenpartitioned between H₂O (70 mL) and DCM (100 mL). The aqueous layer wasfurther extracted with DCM (2×50 mL), and the organic layers werecombined, dried (Na₂SO₄), the solvent was removed and the residue waspurified by Prep HPLC [reverse phase HPLC (CHIRALPAK AD-H, C-18, 250×19mm, 5 um, 15.0 mL per min, gradient 0% to 30% (over 21.0 mins), 0.1%Ammonia in Acetonitrile and 0.1% Ammonia in Water to give ethyl2-{4-[(2S)-1-phenylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-77 Isomer 1 (10 mg, 13%) as a gum, and ethyl2-(4-[(2S)-1-phenylpyrrolidin-2-yl]piperidin-1-yl)-6-azaspiro[3.4]octane-8-carboxylate,Example 2-77 Isomer 2 (10 mg, 13%) as a gum. The data for Isomer 2 arein Table 3.

Route ag Typical Procedure for the Arylation of Pyrrolidine ContainingCompounds with Heterocycles Using Cesium Carbonate and Copper Iodide inDMF as Exemplified by the Preparation of Example 2-78, Methyl2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of methyl2-(4-[(2S)-pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.120 g, 0.37 mmol), Cs₂CO₃ (0.361 g, 1.1 mmol) and CuI (0.105 g, 0.50mmol) were dissolved in DMF (5 mL) and stirred at RT for 30 min.2-Bromopyridine (0.058 g, 0.37 mmol was then added and the resultingmixture was stirred at 100° C. for 18 h. The reaction mixture waspartitioned between H₂O (70 ml) and EtOAc (50 mL). The aqueous layer wasfurther extracted with EtOAc (2×50 mL). The organic layers werecombined, dried (NaSO₄), the solvent was removed by concentration andthe residue was purified Prep HPLC (X Bridge, C-18, 15019 mm, um, 13 mLper min, gradient 40% to 100% (over 20 mins), 0.1% Ammonia inAcetonitrile/water] to give methyl2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateExample 2-78 Isomer 1 (0.011 g, 2%) as a gum, and methyl2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylateExample 2-78 Isomer 2 (0.09 mg, 2%) as a gum. The data for Isomer 2 arein Table 3.

Route ah Typical Procedure for the Arylation of Pyrrolidine ContainingCompounds with Heterocycles Using Sodium Carbonate in Ethanol asExemplified by the Preparation of Example 2-81, Ethyl2-{4-[(2S)-1-(pyrimidin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl(0.100 g, 0.29 mmol) and Na₂CO₃ (0.092 g, 0.87 mmol) were dissolved inethanol (10 mL) and stirred at RT for 30 min. 2-Chloropyrimidine (0.034g, 0.29 mmol) was then added at 0° C. The resulting reaction mixture wasstirred at 80° C. for 6 h. The reaction mixture was concentrated anddichloromethane was added. The mixture was filtered, and the filtratewas concentrated and purified by Prep HPLC (X Bridge, C-18, 150×19 mm, 5um, 15 mL per min, gradient 38% (over 0.01 mins), 42% (over 15.00 mins),100% (over 19.00 mins), then 38% (over 23.00 mins), 0.1% Ammonia inAcetonitrile/water] to give ethyl2-{4-[(2S)-1-(pyrimidin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-81 Isomer 1 (0.031 g, 25%) as a gum, and ethyl2-(4-[(2S)-1-(pyrimidin-2-yl)pyrrolidin-2-yl]piperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylate,Example 2-81 Isomer 2 (0.017 mg, 14%) as a gum. The data for Isomer 2are in Table 3.

Route ai Typical Procedure for the Arylation of Pyrrolidine ContainingCompounds with Heterocycles Using Cesium Carbonate in DMF as Exemplifiedby the Preparation of Example 2-82, Ethyl2-{4-[(2S)-1-(1,34-thiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

The mixture of diastereomers of ethyl2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.HCl.Intermediate 127, (100 mg, 0.27 mmol) was dissolved in DMF (5 mL) andCS₂CO₃ (260 mg, 0.81 mmol) was added to it, followed by the addition of2-bromothiazole (58 mg, 0.29 mmol). The reaction mixture was stirred at90° C. for 16 h. The reaction mixture was partitioned between H₂O (70mL) and EtOAc (50 mL). The aqueous layer was further extracted withEtOAc (2×50 mL). The organic layers were combined, dried (Na₂SO₄), thesolvent was removed by concentration and the residue was purified byPrep HPLC [reverse phase HPLC (CHIRALPAK AD-H, C-18, 250×19 mm, 5 um,15.0 mL per min, gradient 0% to 30% (over 21.0 mins), 0.1% Ammonia inAcetonitrile and 0.1% Ammonia in Water to give ethyl2-{4-[(2S)-1-(1,3-thiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-82 Isomer 1 (20 mg, 18%) as a colorless gum, and ethyl2-{4-[(2S)-1-(1,3-thiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-82 Isomer 2 (6 mg, 6%) as a colorless gum. The data for Isomer1 and Isomer 2 are in Table 3.

Route aj Typical Procedure for the Preparation of Piperidines ViaDeprotection and Reductive Aminations, as Exemplified by the Preparationof Example 2-84, Ethyl2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

tert-Butyl4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.398 g, 1.28 mmol) was dissolved in DCM (1 mL), followed by thedropwise addition of HCl in dioxane (3 mL, 4.0 M solu.). The resultingreaction mixture was stirred at rt for 1 h, the solvents were removed invacuo and the residue was carried on to the next step without furtherpurification. Methyl 1-piperidin-4-yl-D-prolinate.HCl (0.358 g, 1.26mmol) and ethyl 2-oxo-8-azaspiro[3.4]octane-6-carboxylate (0.288 g, 1.26mmol) were dissolved in DMF (4 mL) at it and DIPEA (0.435 mL, 2.510mmol) was added. The reaction mixture was stirred at rt for 3 h. STAB(0.533 g, 2.518 mmol) was then added and the reaction mixture wasstirred overnight under nitrogen at rt. The solvents were removed invacuo, and Preparative HPLC was used to separate the diastereomers,using a Phenomenex Gemini-NX C18 column, 100×30 mm, eluting with 25 to45% MeCN/0.2% ammonia in H₂O (v) at 18 mL/min and collecting fractionsby monitoring at 210 nm to give Example 2-84 Isomer 1 ethyl2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(18.4 mg, 4%) as a colourless oil and Example 2-84 Isomer 2, ethyl2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-8-azaspiro[3.4]octane-6-carboxylate(13.9 mg, 3%) as a colourless oil. The data for Isomer 2 are in Table 3

Route ak Typical Procedure for the Preparation of Piperidines ViaReductive Amination as Exemplified by the Preparation of Example 245,Ethyl2-{4-[(2S)-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

(S)—N-methyl-1-(piperidin-4-yl)pyrrolidine-2-carboxamide dihydrochloride(0.2 g, 0.94 mmol), NEt₃ (0.75 mL, 5.0 mmol),6-(ethoxycarbonyl)-2-oxo-6-azaspiro[3.4]octan-8-ylium (0.188 g, 0.93mmol) and ZnCl₂ (30 mg, 0.02 mmol) were dissolved in MeOH (15.00 mL)under nitrogen and stirred for 1 h at 50-60° C. NaCNBH₃ (0.069 g, 1.0mmol) was added portion wise at 0-10° C. and the reaction mixturestirred for 3 h at room temperature. The reaction mixture waspartitioned between EtOAc (2×50 mL) and water (30 mL), the organiclayers were combined, dried (Na₂SO₄), filtered and the solvent wasremoved in vacuo and the crude product was purified by PREP-HPLC[reverse phase HPLC (X-Bridge PREP C18, 250×19 mm, 5 um, 15 mL per min,gradient 30% to 100% (over 22 min), then 100% (2 min), 0.1% NH, inAcetonitrile to give Example 245 Isomer 1, ethyl(S)-2-(4-(2-(methylcarbamoyl)pyrrolidin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.09 g, 24.32%) as a white solid and Example 2-8 Isomer 2, ethyl(S)-(4-(2-(methylcarbamoyl)pyrrolidin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-8-carboxylate(0.089 g, 24.10%) as a white solid. The data for Isomer 2 are in Table3.

Route ap Typical Procedure for the Preparation of Piperidines ViaDeprotection and Sodium Triacetoxyborohydride Reductive Amination, asExemplified by the Preparation of Example 2-87, ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl}-6-azaspiro[3.4]octane-1-carboxylate

tert-butyl4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidine-1-carboxylate(0.3 g, 1.03 mmol) was dissolved in 4.0M HCl in dioxane (10 mL) and thereaction mixture was stirred at rt for 6 h. The solvents were removed invacuo and the residue was used in the next step without furtherpurification. The crude reaction mixture and ethyl2-oxo-6-azaspiro[3.4]octane-8-carboxylate (0.243 g, 1.233 mmol) weredissolved in DCE (10 mL) at rt and EtN (0.249 g, 2.47 mmol) was added.The reaction mixture was stirred at 50° C. under nitrogen for 2 h. Thereaction mixture was cooled to rt, glacial acetic acid (0.114 g, 1.90mmol) and STAB (0.784 g, 3.69 mmol) were added and the reaction mixturewas stirred overnight at 50° C. under nitrogen. Water (2 mL) was addedto the cooled reaction mixture and the solvents were removed in vacuo.The residue was partitioned between DCM (15 mL) and sat. NaHCO₃ (aq) (15mL), the aqueous layer was washed with DCM (2×15 mL). The organic layerswere combined and dried by passing through a Biotage Phase SeparatorCartridge. The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 10 g 40-63 μm, 60 Å, 12 mL per min, gradient 1% to 10% MeOH/DCM.The residue was further purified by preparative reversed phase HPLC(Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with20 to 50% MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions by monitoring at210 nm) to give ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylate,Example 2-87 Isomer 1 (0.020 g, 4.5%) and ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-87 Isomer 2 (0.020 g, 4.5%). The data for Isomer 2 are inTable 3.

Route am Typical Procedure for the Preparation of Piperidines ViaDeprotection and Amide Formation, as Exemplified by the Preparation ofExample 2-88, Ethyl2-{4-[(2R)-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-87, (0.400 g, 0.932 mmol) was dissolved in THF (8 mL) and 1MLiOH (aq) (1.9 mL) was added, the reaction mixture was stirred at rtovernight. The reaction mixture was neutralised using 2.0 M HCl solutionand solvents were removed in vacuo. The residue was azeotroped withtoluene to give1-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-4,4-difluoro-D-prone(0.440 g, 100%) as a yellow glass.

LCMS (Method C): m/z 415 (M+H)+ (ES+) at 0.71 min, UV inactive

1-{1-[6-(ethoxycarbonyl)-8-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-4,4-difluoro-D-proline(0.193 g, 0.466 mmol, was dissolved in anhydrous DMF (5 mL) and HATU(0.533 g, 1.398 mmol), 2.0M methylamine solution in THF (2.3 mL, 2.33mmol) and DIPEA (0.301 g, 2.33 mmol) were added, the reaction mixturewas stirred overnight at rt. The solvents were removed in vacuo, and theresidue was partitioned between DCM (20 mL) and sat NaHCO₃ (aq) (20 mL),aqueous layer was extracted with DCM (2×15 mL). The organic layers werecombined, washed with brine (20 mL) and dried by passing through aBiotage Phase Separator Cartridge. The solvents were removed in vacuo,and the residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 10 g 40-83 μm, 60 Å, 12 mL per min,gradient 0% to 10% MeOH/DCM]). The residue was further purified bypreparative reversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axiacolumn, 100×30 mm, eluting with 20 to 50% MeCN/Solvent B over 14.4 minat 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] andcollecting fractions by monitoring at 210 nm) to give ethyl2-{4-[(2R)-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-6-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-88 Isomer 1, (0.038 g, 18%) as a colourless oil and ethyl2-{4[(2R-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-88 Isomer 2, (0.037 g, 18%) as a colourless oil. The data forIsomer 2 are in Table 3.

Route an Typical Procedure for the Preparation of Piperidines Via AmideFormation, as Exemplified by the Preparation of Example 2-90, Ethyl2-{4-[(2R)-2-carbamoyl-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Mixture of diastereomers of ethyl2-{4-[(2R)-2-methoxycarbonyl-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(456 mg, 1.062 mmol) was dissolved in THF (1 mL) and 28% NH₃ solution (9mL) at 60° C. and reaction stirred for 18 h. Reaction mixtureneutralized with 1M HCl_((aq)) diluted with DCM (25 mL) and washed withH₂O (2×25 mL), combined aqueous layers washed with DCM (25 ml), combinedorganic layers washed with brine (25 mL) and passed through BiotagePhase separator. Volatiles removed under vacuum to yield an orange oil(0.290 g, 65%). Preparative HPLC was used to separate the diastereomers,using a Phenomenex Gemini-NX C18 column, 100×30 mm, eluting with 20 to45% MeCN/0.2% ammonia in H₂O (v/v) at 18 mL/min and collecting fractionsby monitoring at 210 nm to give Example 2-90 Isomer 1 ethyl2-{4-[(2R)-2-carbamoyl-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-8-carboxylate(16.8 mg 4%) as a colourless oil and Example 2-90 Isomer 2, ethyl2-{4-[(2R)-2-carbamoyl-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(12.4 mg, 3%) as a colourless ol. The data for Isomer 2 are in Table 3

Route ao Typical Procedure for the Preparation of Piperidines ViaHydrolysis and Amide Formation, as Exemplified by the Preparation ofExample 2-91, Ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

Mixture of diastereomers of ethyl2-{4-[(2R)-2-methoxycarbonyl)-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(230 mg, 0.536 mmol) was dissolved in THF (6.5 mL) and 1.0M LiOHsolution (1.1 mL, 1.1 mmol) at rt and reaction stirred for 18 h.Volatiles removed under vacuum and compound carried through withoutfurther purification.1-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-4,4-difluoro-D-proline(125 mg, 0.300 mmol) was dissolved in DMF (1 mL) followed by addition ofHATU (228 mg, 0.60 mmol) and DIPEA (0.260 mL, 1.50 mmol). The reactionmixture was stirred at 0° C. for 10 minutes, followed by addition ofmethoxyamine hydrochloride (25 mg, 0.30 mmol) and resulting reactionmixture was stirred at rt for 18 h. The reaction mixture wasconcentrated in vacuo, then was partitioned between saturatedNaHCO_(3(aq)) (50 mL) and DCM (50 mL), the aqueous layer was furtherextracted with DCM (2×50 mL), the organic layers were combined, washedwith brine (50 mL) and passed through Biotage Phase separator. Volatilesremoved under vacuum to yield an orange oil (0.102 g, 77%). PreparativeHPLC was used to separate the diastereomers, using a PhenomenexGemini-NX C18 column, 100×30 mm, eluting with 20 to 50% MeCN/0.2%ammonia in H₂O (v/v) at 18 mL/min and collecting fractions by monitoringat 210 nm to give Example 2-91 Isomer 1 ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbamoyl)pyrrolidin-1-yl]piperidin-6-yl}-6-azaspiro[3.4]octane-6-carboxylate(12.2 mg, 4%) as a colourless oil and Example 2-91 Isomer 2, ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(7.2 mg, 3%) as a colourless oil. The data for Isomer 2 are in Table 3

Route ap Typical Procedure for the Preparation of Piperidines ViaDeprotection and Sodium Triacetoxyborohydride Reductive Amination, asExemplified by the Preparation of Example 2-111, Ethyl2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

1-Piperidin-4-yl pyrrolidine-2-one (0.200 g, 1.19 mmol) and ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0212 g, 1.14 mmol) weredissolved in DMF (8 mL) at rt, the reaction mixture was stirred at 40°C. under nitrogen for 3 h. The reaction mixture was cooled to it, STAB(0.630 g, 2.97 mmol) and glacial acetic acid (0.071 g, 1.189 mmol) wereadded and the reaction mixture was stirred overnight at 40° C. undernitrogen. Water (2 mL) was added to the cooled reaction mixture and thesolvents were removed in vacuo. The residue was partitioned between DCM(15 mL) and sat. NaHCO₃ (aq) (15 mL), the aqueous layer was washed withDCM (2×15 mL). The organic layers were combined and dried by passingthrough a Biotage Phase Separator Cartridge. The solvents were removedin vacuo, and the residue was purified by column chromatography (normalphase, [Biotage SNAP cartridge KP-sil 10 g 40-63 μm, 60 Å, 12 mL permin, gradient 1% to 10% MeOH/DCM]). The residue was further purified bypreparative reversed phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axiacolumn, 100×30 mm, eluting with 20 to 35% MeCN/Solvent B over 14.4 minat 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O) in H₂O] andcollecting fractions by monitoring at 210 nm) to give ethyl2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-111 Isomer 1. (0.006 g, 2%) as a colourless of and ethyl2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 2-111 Isomer 2, (0.009 g, 2%) as a colourless oil. The data forIsomer 2 are in Table 3.

If amine used in the reductive amination contains a second amine groupwhich is protected (with standard amine protecting groups such as BOC orCbz). Then standard methods for deprotection can be used to remove theseprotecting groups once the reductive amination has been performed toallow further functionalization of the target.

Route aq Typical Procedure for the Preparation of Piperidines ViaReductive Amination, Boc Deprotection and Urea Formation as Exemplifiedby the Preparation of Example 2-124, Ethyl2-[4-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

Ethyl 2-(4-oxopiperidin-1-yl)-8-azaspiro[3.4]octane-6-carboxylatehydrochloride (0.316 g, 1.00 mmol) and tert-butyl(2-aminoethyl)carbamate (0.320 g, 2.00 mmol) were dissolved in DCM (10mL) under N₂ at rt, NEt₃ (0.15 mL, 1.10 mmol) was added and the reactionmixture was stirred at rt for 0.5 h. Acetic acid (0.13 mL, 2.20 mmol)was added, the reaction mixture stirred at rt for 2 h, STAB (0.530 g,2.50 mmol) was added and the reaction mixture stirred overnight. Thereaction mixture was quenched with the addition of NaHCO₃ (sat aq.) (30mL), extracted with DCM (4×25 mL) the combined DCM layers were passedthrough a Biotage phase separator and concentrated in vacuo to givecrude ethyl2-[4-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateas a mixture of diastereomers which was used without any furtherpurification.

LCMS (Method D): m/z 425 (M+H)⁺ (ES+), at 1.30 and 1.35 min, UVinactive.

Crude ethyl2-[4-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate(0.424 g, 1.00 mmol) was dissolved in CH₂Cl₂ (10 ml), 4 M hydrogenchloride in dioxane (1.25 mL, 5.0 mmol) added and the reaction mixturestirred at rt overnight. The volatiles were removed in vacuo, theresidue dissolved in EtOH (10 mL), NEt₃ (1.40 mL, 10.0 mmol) and CDI(0.244 g, 1.50 mmol) added and the mixture heated to reflux andmaintained overnight. The solvent was removed in vacuo, the residuepartitioned between CH₂Cl₂ (20 mL) and water (20 mL) and the aqueouslayer extracted with CH₂Cl₂ (4×20 mL). The combined organics wereconcentrated in vacuo to give crude ethyl2-[4-(2-oxoimidazolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateas a mixture of diastereomers. Preparative HPLC was used to separate thediastereomers, using a Phenomenex Gemini-N C18 column, 150×21 mm,eluting with 25 to 45% MeCN in 0.2% NH₃/H₂O at 18 mL/min and collectingfractions by monitoring at 210 nm to give ethyl2-[4-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-8-carboxylate,Example 2-124 Isomer 1, (0.008 g, 2.3%) as a colourless solid and ethyl2-[4-(2-oxo-1,2-dihydropyridin-4-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 2-124 Isomer 2, (0.008 g, 2.3%) as a colourless solid. The datafor Isomer 2 are in Table 3.

Route ar Typical Procedure for the Preparation of Piperidines Via EsterReduction, as Exemplified by the Preparation of Example 2-136, Ethyl2-{4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate

A mixture of diastereomers of ethyl2-{4-[(2R,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate(0.140 g, 0.341 mmol) was dissolved in anhydrous THF (10 ml) and cooledto 0° C. under nitrogen. 2.0 M Lithium borohydride solution in THF (1.02mL, 1.023 mmol) was added dropwise to the reaction mixture and then thereaction mixture was allowed to warm to rt overnight. The reactionmixture was quenched with sat. NaHCO₃ (aq) (15 ml) and then extractedwith EtOAc (2×15 mL), the organic layers were combined and dried(MgSO₄). The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 10 g 40-63 μm, 60 Å, 12 ml per min, gradient 0% to 10%MeOH/DCM]). The residue was further purified by preparative reversedphase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm,eluting with 20 to 50% MeCN/Solvent B over 14.4 min at 30 mL/min [wheresolvent B is 0.2% of (28% NH/H₂O) In H₂O] and collecting fractions bymonitoring at 210 nm) to give ethyl2-{4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-136 Isomer 1, (2.99 mg, 0.23%) as a white solid and ethyl2-{4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,Example 2-136 Isomer 2, (3.10 mg, 0.24%) as a white solid. The data forIsomer 2 are in Table 3.

Route as Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination in DMF as Exemplified by thePreparation of Example 3-4, Ethyl2-[4-(3-hydroxypyridin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

2-(Piperidin-4-yl)pyridin-3-ol dihydrochloride (0.20 g, 0.8 mmol) andethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.157 g, 0.8 mmol) weremixed in DMF (8 mL) at rt. DIPEA (0.28 mL, 1.6 mmol) and AcOH (0.07 mL,12 mmol) were added, followed by STAB (0.34 g, 1.6 mmol). The reactionmixture was stirred under nitrogen at rt overnight, then quenched withthe addition of a small quantity of MeOH, and concentrated in vacuo toremove all the solvents. The residue was dissolved in a mixture of MeOHand DCM and concentrated onto flash silica (˜10 mL) In vacuo. Theresulting powder was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 25 g, 40-3 μm, 60 Å, 30 mL per min,gradient 0% to 15% Solvent A in DCM over 15 column volumes, wheresolvent A is 10% of (7 M NH₃/MeOH) In MeOH]) to give a crude mixture ofdiastereomers (0.258 g). This mixture was dissolved in MeOH, a smallquantity of 28% NH₃/H₂ was added (˜0.1 mL), and the solution waspurified by preparative reversed phase HPLC using a Phenomenex Gemini-NX5 μm C18 110A Axia column, 100×30 mm, eluted with 15 to 25% MeCN/SolventB over 14.4 min at 30 mL/min [where solvent B is 0.2% of (28% NH₃/H₂O)in H₂O] and collecting fractions by monitoring at 230 nm to give ethyl2-[4-(3-hydroxypyridin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Example 3-4 Isomer 1. (0.034 g, 12%) and ethyl2-[4-(3-hydroxypyridin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Example 3-4 Isomer 2, (0.052 g, 18%). The data for Isomer 2 are in Table3.

Route at Typical Procedure for the Preparation of Piperidines Via SodiumTriacetoxyborohydride Reductive Amination as Exemplified by thePreparation of Example 3-10, Ethyl2-[4-cyano-(pyridine-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

4-(Pyridin-2-yl)piperidine-4-carbonitrile hydrochloride (0.187 g, 1.0mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.197 g, 10mmol) were dissolved in DCM (10 mL) under N₂ at rt and NEt₃ (0.15 mL,1.1 mmol) was added. The reaction mixture was stirred at rt for 1 h,acetic acid (0.13 mL, 2.2 mmol was added and the reaction mixturestirred at rt for 3 h. STAB (0.636 g, 3.0 mmol) was added and thereaction mixture stirred overnight. The reaction mixture was quenchedwith the addition of NaHCO₃ (sat aq.) (30 mL), extracted with DCM (4×25mL) and the combined DCM layers passed through a Biotage phaseseparator. The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase. [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 40 mL per min, gradient 0% to 10% MeOH inDCM) to give an inseparable mixture of diastereomers of ethyl2-[4-cyano-(pyridine-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Preparative HPLC was used to separate the diastereomers, using aPhenomenex Gemini-N C18 column, 150×21 mm, eluting with 25 to 65%MeOH/H₂O at 18 mL/min and collecting fractions by monitoring at 210 nmto give ethyl2-[4-cyano-(pyridine-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 3-10 Isomer 1, (0.012 g, 3%) as a colourless solid and ethyl2-[4-cyano-(pyridine-2-yl)piperidin-1-yl]-6-azaspiro[3]octane-6-carboxylate,Example 3-10 Isomer 2, (0.014 g, 4%) as a colourless solid. The data forboth Isomers are in Table 3.

Route au Typical Procedure for the Preparation of Piperidines ViaAlkylation as Exemplified by the Preparation of Example 4-6, Ethyl2-(1-ethyl-2-oxo-3,4′-bipiperidin-1′-yl)-6-azaspiro[3.4]octane-6-carboxylate

Ethyl2-(2-oxo-[3,4′-bipiperidin]-1′-yl)-6-azaspiro[3.4]octane-carboxylate,Example 4-1, (0.2 g, 0.55 mmol), was dissolved in DMF (3 mL) and cooledto 0-5° C. Sodium hydride (0.080 g, 1.8 mmol) and iodoethane (0.139 g,0.8 mmol, were added and the reaction mixture stirred at roomtemperature for 3 h. The reaction was quenched with water (50 mL),extracted with EtOAc (3×30 mL), and the combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo to give crude ethyl2-(1-ethyl-2-oxo-3,4′-bipiperidin-1′-yl)-6-azaspiro[3.4]octane-6-carboxylateas a mixture of diastereomers. The crude product was purified by prep.HPLC [X-Bridge C18 (150×19 mm, 5 um, 17 mL per min, gradient 27% to 100%(over 30 min), then 100% (4 min), 0.1% NH₃ in acetonitrile to give ethyl2-(1-ethyl-2-oxo-[3,4′-bipiperidin]-1′-yl)-6-azaspiro[3.4]octane-8-carboxylateExample 4-5 Isomer-1 (0.011 g, 5.11%) as a colorless gum and ethyl2-(1-ethyl-2-oxo-[3,4′-bipiperidin]1′-yl)-6-azaspiro[3.4]octane-6-carboxylateExample 4-6 Isomer-2 (0.012 g, 5.80%) as a colorless gum. The data forIsomer 2 are in Table 3.

Route av Typical Procedure for the Preparation of Piperidines Vie SodiumTriacetoxyborohydride Reductive Amination as Exemplified by thePreparation of Example 4-8, Ethyl2-[4-(2-oxotetrahydropyrimidin-1(2H)-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

1-(Piperidin-4-yl)tetrahydropyrimidin-2(1H)-one (0.183 g, 1.0 mmol) andethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.197 g, 1.0 mmol) weredissolved in DCM (10 mL) under N₂ at rt, acetic acid (0.13 mL, 2.2 mmol)was added and the reaction mixture stirred at rt for 3 h. STAB (0.530 g,2.5 mmol) was added and the reaction mixture stirred overnight. Thereaction mixture was quenched with the addition of NaHCO₃ (sat aq.) (30mL), extracted with DCM (4×25 mL) and the combined DCM layers passedthrough a Biotage phase separator. The solvents were removed in vacuo,and the residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 40 mL per min,gradient 0% to 10% MeOH in DCM) to give an inseparable mixture ofdiastereomers of ethyl2-[4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.Preparative HPLC was used to separate the diastereomers, using aPhenomenex Gemini-N C18 column, 150×21 mm, eluting with 15 to 30% MeCNin 0.2% NH₃/H₂O at 18 mL/min and collecting fractions by monitoring at210 nm to give ethyl2-[4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl]-8-azaspiro[3.4]octane-6-carboxylate,Example 4-8 Isomer 1, (0.028 g, 7.7%) as a colourless solid and ethyl2-[4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 4-8 Isomer 2, (0.025 g, 6.9%) as a colourless solid.

The data for both isomers are in Table 3.

Route aw Typical Procedure for the Preparation of Piperidines ViaDeprotection and Sodium Triacetoxyborohydride Reductive Amination, asExemplified by the Preparation of Example 4-13, Ethyl2-(3,3-difluoro-1,4′-bipiperidin-1′-yl)-6-azaspiro[3.4]octane-carboxylate

tert-Butyl 3,3-difluoro-1,4′-bipiperidine-1′-carboxylate (0.347 g, 1.14mmol) was dissolved in 4.0 M HCl in dioxane (5 mL) and the reactionmixture was stirred at rt overnight. The solvents were removed in vacuoand the residue was used in the next step without further purification.The crude reaction mixture and ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.212 g, 1.14 mmol) weredissolved in DMF (6 ml) at rt and DIPEA (0.295 g, 2.28 mmol) was added.The reaction mixture was stirred at 50° C. under nitrogen for 2 h. Thereaction mixture was cooled to rt, glacial acetic acid (0.068 g, 1.14mmol) and STAB (0.804 g, 2.85 mmol) were added and the reaction mixturewas stirred overnight at 50° C. under nitrogen. Water (2 mL) was addedto the cooled reaction mixture and the solvents were removed in vacuo.The residue was partitioned between DCM (15 ml) and sat. NaHCO₃ (aq) (15mL), the aqueous layer was washed with DCM (2×15 mL). The organic layerswere combined and dried by passing through a Biotage Phase SeparatorCartridge. The solvents were removed in vacuo, and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 10 g 40-83 μm, 60 Å, 12 mL per min, gradient 1% to 10%MeOH/DCM]). The residue was further purified by preparative reversedphase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm,eluting with 30 to 60% MeCN/Solvent B over 14.4 min at 30 mL/min [wheresolvent B is 0.2% of (28% NH₃/H₂O) in H₂O] and collecting fractions bymonitoring at 210 nm) to give ethyl2-(3,3-difluoro-1,4′-bipiperidin-1′-yl)-6-azaspiro[3.4]octane-8-carboxylate,Example 4-13 Isomer 1, (0.011 g, 2.6%) as a colourless oil and ethyl2-(3,3-difluoro-1,4-bipiperidin-1′-yl)-6-azaspiro[3.4]octane-6-carboxylate,Example 4-13 Isomer 2, (0.005 g, 1.3%) as a colourless oil. The data forIsomer 2 are in Table 3.

Route ax Typical Procedure for the Preparation of Piperidines ViaReductive Amination as Exemplified by the Preparation of Example 4-16,Ethyl2-[(2R)-2-methylcarbamoyl)-1,4′-bipiperidin-1′-yl]-6-azaspiro[3.4]octane-6-carboxylate

To a solution of (R)—N-methyl-[1,4′-bipiperidine]-2-carboxamide (200 mg,0.890 mmol) and ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (175mg, 0.890 mmol) in DCM (7.5 mL), Ti(O_(i)Pr)₄ (0.80 mL, 2.67 mmol) wasadded at 0° C. and the reaction mixture was stirred for 1 h. Na(OAc)₃BH(562 mg, 2.67 mmol) was added portion wise to the reaction mixture andstirred at 0° C. for 2 h. After completion, the reaction mixture wasquenched with aq sat NaHCO₃ and extracted with DCM (3×30 mL). Theorganic layers were combined and washed with brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by prep-HPLC (reversephase, X BRIDGE, C-18, 19×250 mm, 5μ, gradient 10% to 90% ACN in watercontaining 5 mM NH₄OAc, to give 25 mg (7%) of ethyl2-[(2R)-2-(methylcarbamoyl)-1,4′-bipiperidin-1′-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 4-16 Isomer-1 and 25 mg (7%) of ethyl2-[(2R)-2-(methylcarbamoyl)-1,4′-bipiperidin-1′-yl]-6-azaspiro[3.4]octane-6-carboxylateExample 4-16 Isomer-2 as colorless semisolids. The data for Isomer 2 arein Table 3.

Route ay Typical Procedure for the Preparation of Piperidines ViaAlkylation, Cyclisation and Sodium Triacetoxyborohydride ReductiveAminations, as Exemplified by the Preparation of Example 5-1, Ethyl2-[4-(2-oxoazepan-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate

To a solution of 4-Amino-1-Boc-piperidine (200 mg, 1.0 mmol) in THF (2mL) was added triethylamine (0.153 mL, 1.1 mmol) and 6-Bromohexanoylchloride (0.168 mL, 1.098 mmol) and cloudy suspension was stirred at rtfor 2 h. The solvents were removed in vacuo, and residue was partitionedbetween H₂O (15 mL) and EtOAc (25 mL), aqueous layer was extracted withEtOAc (2×25 mL), organic layers were combined, dried over Na₂SO₄ andsolvent was removed in vacuo to give tert-butyl4-[(6-bromohexanoyl)amino]piperidine-1-carboxylate (378 mg, >99%) as anorange oil.

tert-butyl 4-[(6-bromohexanoyl)amino]piperidine-1-carboxylate (378 mg,1.0 mmol) was dissolved in DMF (25 ml) and sodium hydride was added (48mg, 1.2 mmol). The reaction mixture was stirred at 80° C. for 1 h, thesolvent was removed in vacuo and the residue was was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63μm, 60 Å, 25 mL per min, 1% to 10% MeOH in DCM]) to give tert-butyl4-(2-oxoazepan-1-yl)piperidine-1-carboxylate (178 mg, 60%). The residuewas dissolved in DCM (1 mL), followed by the dropwise addition of HCl indioxane (3 mL, 4.0 M solu.). The resulting reaction mixture was stirredat t for 1 h, the solvents were removed in vacuo and the residue wascarried on to the next step without further purification.1-(piperidin-4-yl)azepan-2-one.HCl (0.182 g, 0.738 mmol) and ethyl2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0.155 g, 0.785 mmol) weredissolved in DMF (2 ml) at it and DIPEA (0.136 mL, 0.790 mmol) wasadded. The reaction mixture was stirred at rt for 3 h. STAB (0.332 g,1.569 mmol) was then added and the reaction mixture was stirredovernight under nitrogen at rt. The solvents were removed in vacuo andthe residue was purified by preparative reversed phase HPLC (PhenomenexGemini-NX 5 μm C18 110A Axia column, 100×30 mm, eluting with 25 to 45%MeCN/Solvent B over 14.4 min at 30 mL/min [where solvent B is 0.2% of(28% NH/H₂) in H₂O] and collecting fractions by monitoring at 210 nm) togive ethyl2-[4-(2-oxoazepan-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 5-1 Isomer 1 (6.2 mg, 2%) as a colourless oil and ethyl2-[4-(2-oxoazepan-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,Example 5-1 Isomer 2 (3.9 mg, 1%) as a colourless oil. The data forIsomer 2 are in Table 3.

TABLE 2 Characterising data and commercial sources for startingmaterials and intermediates Interm ediate Route Name Data 16-Boc-2-oxo-6- Commercially available, azaspiro[3.4]oclane CAS:203661-71-6 2 ethyl 2-oxo-6- ¹H NMR: (400 MHz, CDCl₃) δ:azaspiro[3.4]octane- 1.27 (t, J = 7.0 Hz, 3H), 2.08 (t, 6-carboxylate J= 6.2 Hz, 2H), 2.94-3.17 (m, 4H), 3.49-3.59 (m, 4H), 4.15 (q, J = 7.0Hz, 2H) 3 methyl 2-oxo-6- ¹H NMR: (400 MHz, CD₃OD) δ::azaspiro[3.4]octane- 2.06-2.15 (m, 2 H), 2.94-3.04 (m, 6-carboxylate2H), 3.05-3.17 (m, 2 H), 3.47 (td, J = 6.8, 2.5 Hz, 2 H), 3.54 (d, J =2.5 Hz, 2 H), 3.69 (s, 3 H) 4 2-fluoroethyl 2-oxo- LCMS (Method F): m/z216 6-azaspiro[3.4]octane- (M + H)⁺ (ES+) at 1.79 min, 6-carboxylate UVinactive 5 4-(1H-imidazol-2-yl) Commercially available, piperidine CAS:90747-46-9 dihydrochloride 6 4-(1-methylimidazol-2- Commerciallyavailable, yl)piperidine CAS: 1198420-89-1 hydrochloride 74-(1H-pyrazol-5- Commercially available, yl)piperidine CAS: 278798-08-68 5-(piperidln-4-yl)- Commercially available, 1H-pyrazol-3- CAS:1325671-21-3 amine 9 4-(1-methyl- Commercially available, 1H-pyrazol-5-CAS: 640270-01-5 yl)pipendine 10 4-(1-methyl-1H- Commercially available,pyrazol-3- CAS: 1211527-48-8 yl)piperidine 11 4-(1H-pyrrol-1-Commercially available, yl)piperidine CAS: 169751-01-3 12 4-(1H-pyrazol-Commercially available, 1-yl)piperidine CAS: 762240-09-5 134-(4-methyl-1H- Commercially available, pyrazol-1- CAS: 1211520-55-6yl)pipendine 14 4-(Pyridin-2-yl) Commercially available, piperidine-4-CAS: 767263-33-2 carbonitrile hydrochloride 15 4-(1-Methylimidazol-Commercially available, 2-yl)piperidine CAS: 1198420-89-1 hydrochloride16 4-(1H-1,2,4- Commercially available, Triazol-1-yl) CAS: 158655-26-6piperidine 17 4-(1H-1,2,4-Triazol- Commercially available,3-yl)piperidine CAS: 1417359-91-1 hydrochloride 18 4-(1H-1,2,3-Triazol-Commercially available, 1-yl)piperidine CAS: 690261-88-2 hydrochloride19 2-(piperidin-4-yl) Commercially available, pyridin-3-ol CAS:1260650-52-9 dihydrochloride 20 4-(5-chloro-1-methyl- LCMS (Method C):1H-imidazol-2-yl) m/z 200/202 (M + H)⁺ piperidine (ES+), at 1.33 min,trifluoroacetate UV active 21 4-(4,5-dichloro-1- LCMS (Method C): m/zmethyl-1H-imidazol- 234/236/238 (M + H)⁺ 2-yl)piperidine (ES+), at 1.53min, trifluoroacetate UV active 22 4-(5-chloro-1H- LCMS (Method C): m/zimidazol-2-yl) 186/188 (M + H)⁺ (ES+), piperidine at 0.32 min. UV activedihydrobromide 23 4-(5-ethyl-1H- Commercially available,1,2,4-triazol-3- CAS: 1432680-84-6 yl)piperidine hydrochloride 244-methyl-4-(3- Commercially available, methyl-1,2,4- CAS: 1361112-08-4oxadiazol-5- yl)piperidine hydrochloride 25 4-(4,5-dichloro- m/z220/222/224 (M + H)⁺ 1H-imidazol-2- (ES+), at 0.54 min. yl)piperidine UVactive dihydrobromide 26 2-(piperidin-4- Commercially available,yl)pyrimidin-4- CAS: 1461714-43-1 amine dihydrochloride 27 ethyl4-(1H-imidazol- Commercially available, 2-yl)piperdine-1- CAS:1198420-87-9 carboxylate 28 tert-butyl 4-(4,4,5,5- Commerciallyavailable, tetramethyl-1,3,2- CAS: 286961-14-6 diaxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate 29 2-5-bromo-1,2,4- Commerciallyavailable, thiadiazole CAS: 43201-13-4 39 Route 1 and5-(piperidin-4-yl)- LCMS (Method G): m/z intermediates 1,2,4-thiadiazole170 (M + H)⁺ (ES+), at 28 and 29 3.761 min, UV active 314-(1H-tetrazol-5- Commercially available, yl) piperidine CAS:112626-97-8 32 4-(1H-pyrazol- Commercially available, 1-yl)piperidineCAS: 762240-09-5 33 4-[4-(trifluoromethyl)- LCMS (Method F): m/z1H-imidazol-2-yl] 220 (M + H)⁺ (ES⁺), at piperidine hydrochloride 2.16min, UV active 34 4-(1,5-dimethyl-1H- LCMS (Method G): m/zimidazol-2-yl)-1,2,3,6- 178 (M(ES+), at 3.90 tetrahydropyridine min, UVactive hydrochloride 36 2-bromo-1,4-dimethyl- Commercially available,1H-imidazole CAS: 235426-30-9 36 Route 2 and 4-(1,4-dimethyl-1H- LCMS(Method G): m/z intermediate imidazol-2-yl)- 178 (M + H)⁺ (ES⁺), at 351,2,3,6-tetrahydropyridine 3.80 min, UV active 37 4-[1-methyl-4- LCMS(Method F): m/z (trifluoromethyl)-1H- 234 (M + H)⁺ (ES⁺), atimidazol-2-yl]piperidine 1.48 min, UV active hydrochloride salt 384-(1-methyl-1H- Commercially available, pyrazol-5-yl) CAS: 640270-01-5pipendine 39 2-bromooxazole Commercially available, CAS: 125533-82-6 402-bromothiazole Commercially available, CAS: 3034-53-5 41 Route 1 and4-(1,3-oxazol-2- LCMS (Method H): m/z intermediate yl)piperidine 153(M + H)⁺ (ES⁺), at 39 7.92 min, UV active 42 Route 1 and4-(1,3-thiazol-2- LCMS (Method H): m/z intermediate yl)piperidine 169(M + H)⁺ (ES⁺), at 40 7.53 min, UV active 43 4-(1,3,4-oxadiazol- ¹H NMR:(400 MHz, 2-yl) piperidine CDCl³) δ: 1.78-1.90 (m, 2H), 1.98-2.16 (m,2H), 2.70-2.85 (m, 2H), 3.02- 3.16 (m, 1H), 3.16-3.27 (m, 2H), 8.35 (s,1H), NH not observed 44 4-(3-methyl-1,2,4- LCMS (Method H): oxadiazol-5-m/z 168 (M + H)⁺ yl) piperidine (ES⁺) at 5.80 min, UV active 45tert-butyl 4- Commercially available, formylpiperidine- CAS: 137076-22-31-carboxylate 46 tert-butyl 4-[4- LCMS (Method F): m/z(trifluoromethyl)- 320 (M + H)⁺ (ES⁺), 1H-imidazol-2-yl] at 2.16 min, UVactive piperidine-1-carboxylate 47 4-(1H-imidazol-2- LCMS (Method G):m/z yl)piperidin-4-ol 168 (M + H)⁺ (ES⁺), at hydrochloride salt 2.46min, UV active 48 4-(1H-imidazol-2- LCMS (Method G): m/z yl)-4-methoxy-162 (M + H)⁺ (ES⁺), at piperidine 2.87 min, UV active hydrochloride salt49 4-(1-methyl-1H- LCMS (Method G): m/z imidazol-2-yl) 132 (M + H)⁺(ES⁺), at piperidin-4-ol 3.09 min, UV active hydrochloride salt 504-methoxy-4-(1- LCMS (Method G): m/z methyl-1H-imidazol- 196 (M + H)⁺(ES⁺), at 2-yl)piperidine 3.35 min, UV active hydrochloride salt 51(S)-Tert-butyl 2- Commercially available, (piperidin-4-yl) CAS:1449131-15-0 pyrrolidine-1- carboxylate 52 (R)-Tert-butyl 2-Commercially available, (piperidin-4-yl) CAS: 1451390-44-5pyrrolidine-1- carboxylate 53 Tert-butyl 2- Commercially available,(piperidin-4-yl) CAS: 929974-12-9 pyrrolidine-1- carboxylate 54Propionyl Chloride Commercially available, CAS: 79-03-8 55 Methylchloroformate Commercially available, CAS: 79-22-1 55 Ethylchloroformate Commercially available, CAS: 541-41-3 57 Methylaminoformylchloride Commercially available, CAS: 6452-47-7 58 Dimethylaminoformylchloride Commercially available, CAS: 79-44-7 59 Cydopropanecarbonylchloride Commercially available, CAS: 4023-34-1 60 Cyclobulanecarbonylchloride Commercially available, CAS: 5006-22-4 61 Acetyl chlorideCommercially available, CAS: 75-36-5 62 Ethyl 2,2,2-trifiuoraacetateCommercially available, CAS; 383-63-1 63 Acetic Anhydride Commerciallyavailable, CAS: 108-24-7 64 3-iodo-2-methoxypyridine Commerciallyavailable, CAS: 112197-15-6 65 Route 3 and 3-(piperidine-4-yl) ¹H NMR:(400 MHz, intermediates pyridin-2-ol DMSO-d₆) δ: 1.70-2.00 28 and 64 (m,4H), 2.84-3.15 (m, 3H), 3.32 (d, J = 12.5 Hz, 2H), 7.00 (dd, J = 7.3 and5.2 Hz, 1H), 7.53 (dd, J = 7.3 and 1.5 Hz, 1H), 8.06 (dd, J = 5.2 and1.5 Hz, 1H), 8.93- 9.39 (m, 2H) 66 Route 4 and 2-methoxy-3-(piperidin-4-LCMS (Method F): m/z intermediates yl)pyridine 193 (M + H)⁺ (ES+), at 28and 64 6.19 min, UV active 67 5-bromo-2-methoxy-4- Commerciallyavailable, methylpyridine CAS: 164513-39-7 68 5-bromo-2-methoxy-3-Commercially available, methylpyridine CAS: 760207-87-2 69 Route 5 and3,4′-bipiperidln-2-one LCMS (Method F): m/z intermediate 183 (M + H)⁺(ES+), 65 at 0.32 min, UV active 70 4-(piperidin-4-yl) Commerciallyavailable, pyrimidin-2-amine CAS: 1211632-88-5 71 Route 4 and2-methoxy-4-methyl- LCMS (Method F): m/z intermediates5-(piperidin-4-yl) 207 (M + H)⁺ (ES+), 28 and 67 pyridine at 1.44 min,UV active 72 Route 4 and 2-methoxy-3-methyl- LCMS (Method F): m/zintermediates 5-(piperidin-4-yl) 207 (M + H)⁺ (ES+), at 28 and 88pyridine 1.59 min, UV active 73 4-(4-methyl-1H- Commercially available,pyrazol-1-yl) CAS: 1211520-55-5 piperidine 74 4-Isoxazol-3-yl-Commercially available, piperidine CAS: 1060814-32-5 75 N-[(benzyloxy)Commercially available, carbonyl]-N- CAS: 39608-31-6 methylglycine 76Methoxyamine Commercially available, hydrochloride CAS: 593-58-6 77Isopropylamine Commercially available, CAS: 75-31-0 782,2,2-Trifluoroethyiamine Commercially available, CAS: 753-90-2 79Azetidine Commercially available, CAS: 503-29-7 80 MorpholineCommercially available, CAS: 110-91-8 81 Cyclopropylamine Commerciallyavailable, CAS: 765-30-0 82 Cyclobutylamine Commercially available, CAS:2516-34-9 83 2-methoxyethylamine Commercially available, CAS: 109-85-384 Pyrrolidine Commercially available, CAS: 123-75-1 85N,O-dimethylhydroxy- Commercially available, lamine hydrochloride CAS:6538-79-5 86 1-methylcyclobutan- Commercially available, 1-aminehydrochloride CAS: 174886-05-6 87 3-amino-3-methyloxetane Commerciallyavailable, CAS: 874473-14-0 88 3,3-difluoropyrrolidine Commerciallyavailable, hydrochloride CAS: 163457-23-6 89 3,3-difluorocyclobutanamineCommercially available, hydrochloride CAS: 637031-93-7 903,3-difluoroazetidine Commercially available, hydrochloride CAS:288315-03-7 91 tert-Butyl carbazate Commercially available, CAS:870-46-2 92 cyclobutanol Commercially available, CAS: 2919-23-5 932-fluoroethylamine Commercially available, hydrochloride CAS 460-06-2 942,2-difluoroethylamine Commercially available, CAS: 430-67-1 95methoxyacetyl chloride Commercially available, CAS: 38870-89-2 962-fluoroethyl chloroformate Commercially available, CAS: 462-27-1 972,2,2-trifluoroethyl Commercially available, chloroformate CAS:27746-99-2 98 methyl chlorothiolformate Commercially available, CAS:18369-83-0 99 2-methoxyethanol Commercially available, CAS: 109-85-4 1002~dimethylaminoethanol Commercially available, CAS: 108-01-0 101 acetoxyacetyl chloride Commercially available, CAS: 13831-31-7 1023,3,3-trifiuoropropionic acid Commercially available, CAS: 2516-99-6 1032-(aminomethyl) pyridine Commercially available, CAS: 3731-51-9 1042,2,2-Trifluoro-N- Commercially available, methylethanamine CAS:2730-52-1 hydrochloride 105 oxetan-3-ylamine Commercially available,CAS: 21635-88-1 106 N-methyl-3-aminooxetane Commercially available, CAS:952182-03-5 107 Lawesson Reagent Commercially available, CAS: 19172-47-5108 (2S,4R)-1-Boc-4-hydroxy Commercially available,pyrrolidine-2-carboxylic CAS: 102195-79-9 acid methyl ester 109 triethylphosphono acetate Commercially available, CAS: 867-13-0 110 ethylcyanoacetate Commercially available, CAS: 105-56-8 111 Intermediatesbenzyl 4-[(2S,4R)-1-(tert- LCMS (Method D): m/z 108, 109butoxycarbonyl)-4- 405 (M + H)⁺ (ES+), at and 110hydroxypyrrolidin-2-yl] 1.98 min, UV active piperidine-1-carboxylate 112Intermediate tert-butyl (2S,4S)-4-fluoro- LCMS (Method D): m/z 1112-(piperidin-4-yl) 273 (M + H)⁺ (ES+), at pyrrolidine-1-carboxylate 1.80min, UV active 113 Intermediate tert-butyl (2S)-4,4-difluoro- LCMS(Method D): m/z 111 2-(piperidin-4-yl)pyrrolidine- 291 (M + H)⁺ (ES+),at 1-carboxylate 1.88 min, UV active 114 iodoethane Commerciallyavailable, CAS: 75-03-6 115 D-proline methyl ester Commerciallyavailable, hydrochloride CAS: 65365-28-8 116 2 pyridine propionic acidCommercially available, CAS: 15197-75-8 117 2-[(methylamino)methyl]Commercially available, pyridine CAS: 21035-59-6 118 2-pyridinemethanolCommercially available, CAS: 586-98-1 119 piperidine, 4-(3-methyl-Commercially available, 1H-pyrazol-1-yl)- CAS: 1138819-53-0 120piperidine, 4-(1-ethyl-1H- Commercially available, pyrazol-5-yl)- CA3:442876-34-8 121 (R)-1-tert-Butyl 2-methyl Commercially available,4-oxopyrrolidine-1,2- CAS: 256487-77-1 dicarboxylate 122 Route 6 andEthyl 2-[4-(pyrrolidin-2- LCMS (Method D): m/z intermediatesyl)piperidin-1-yl]-6- 350 (M + H)⁺ (ES⁺), at 2 and 53azaspiro[3.4]octane-6- 2.64 min, UV inactive carboxylate•HCl 123O-Methylhydroxylamine Commercially available, hydrochloride CAS:593-56-6 124 N,O-Dimethylhydroxyl- Commercially available, aminehydrochloride CAS: 6338-78-5 125 Intermediate tert-butyl (2S)-4,4- LCMS(Method C): m/z 257 difluoro-2-methyl- 222 (M + H)⁺ (ES+), atpyrrolidine-1-carboxylate 1.97 min, UV inactive 126 Intermediatetert-butyl (2R)-4,4-difluoro- LCMS (Method C): m/z 121 2-(hydroxymethyl)238 (M + H)⁺ (ES+), at pyrrolidine-1-carboxylate 1.63 min, UV inactive127 Route 6 and Ethyl 2-{4-[(2S)-pyrrolidin- LCMS (Method G): m/zintermediates 2-yl]piperidin-1-yl}-6- 336 (M + H)⁺ (ES⁺), at 2 and 51azaspiro[3.4]octane-6- 6.23 min, UV inactive carboxylate•HCl 1283-bromo-2-methoxy-5- Commercially available, methylpyridine CAS:717843-56-6 129 Route 4 and 2-methoxy-5-methyl-3- LCMS (Method C): m/zintermediate (piperidin-4-yl)pyridine 207 (M + H)⁺ (ES+), at 28 and 127hydrochloride 1.62 min, UV active 130 iodomethane Commerciallyavailable, CAS: 79099-07-3 131 3-aminopropan-1-ol Commerciallyavailable, CAS: 156-87-6 132 Intermediates 3-(piperidin-4-yl)-1,3- LCMS(Method D): m/z 131 and 150 oxazinan-2-one 185 (M + H)⁺ (ES+), athydrochloride 0.29 min, UV inactive 133 3-bromo-2-methoxy-4-Commercially available, methylpyridine CAS: 717843-51-1 134Intermediates 2-methoxy-4-methyl-3- LCMS (Method F): m/z 28 and 133(piperidin-4-yl) pyridine 207 (M + H)⁺ (ES+), at hydrochloride 1.56 min,UV active 135 benzyl 4-oxopiperidine- Commercially available,1-carboxylate CAS: 185847-84-1 136 tert-butyl (3-amino- Commerciallyavailable, propyl)carbamate CAS: 75178-95-0 137 Route 7 and1-(piperidin-4-yl)tetra- LCMS (Method B): m/z intermediateshydropyrimidin-2(1H)-one 184 (M + H)⁺ (ES+), at 135 and 136 4.28 min, UVinactive 138 (S)-N-methylpyrrolidine- Commercially available,2-carboxamide hydrochloride CAS: 33208-98-9 139 Route 8 and(S)-N-methyl-1-(piperidin-4-yl) LCMS (Method G): m/z intermediatespyrrolidine-2-carboxamide 212 (M + H)⁺ (ES+), at 138 and 150dihydrochloride 6.65 min, UV inactive 140 2-bromo-6-methoxypyridineCommercially available, CAS: 40473-07-2 141 Route 4 and2-methoxy-6-(piperidin-4-yl) LCMS (Method G): m/z intermediates pyridinehydrochloride 193 (M + H)⁺ (ES+), at 28 and 140 0.65 min, UV active 1423-bromo-2-methoxy-5- Commercially available, methylpyridine CAS:717843-56-6 143 Route 3 and 5-methyl-3-(piperidin-4- LCMS (Method F):intermediates yl)pyridin-2(1H)-one- m/z 193 (M + H)⁺ (ES+), 28 and 142hydrochloride at 0.276 min, UV active 144 Route 5 and5-methyl-[3,4′-bipiperidin]- LCMS (Method J): m/z intermediate 2-one 197(M + H)⁺ (ES+), at 143 4.05 min, UV inactive 145 3-bromo-2-methoxy-4-Commercially available, methylpyridine CAS: 717843-51-1 146 Route 3 and4-methyl-3-(piperidin-4- LCMS (Method I): m/z intermediatesyl)pyridin-2(1H)-one 193 (M + H)⁺ (ES+), at 25 and 145 hydrochloride2.82 min, UV active 147 Route 5 and 4-methyl-[3,4′-bipiperidin]- LCMS(Method I): m/z intermediate 2-one 197 (M + H)⁺ (ES+), at 146 3.14 min,UV inactive 148 tert-butyl (3-amino-2,2- Commercially available,dimethylpropyl)carbamate CAS: 292606-35-0 149 Route 7 and5,5-dimethyl-1-(piperidin-4- LCMS (Method D): m/z intermediatesyl)tetrahydropyrimidin-2(1H)- 212 (M + H)⁺ (ES+), at 135 and 148 one0.70 min, UV inactive 150 1,4-dioxa-8-azaspiro[4.5] Commerciallyavailable, decane CAS: 74-88-4 151 Intermediates ethyl2-(4-oxopiperidin-1- LCMS (Method D): m/z 2 and 150yl)-6-azaspiro[3,4]octane- 231 (M + H)⁺ (ES+), at 6-carboxylate 0.992min and 1.04 min, UV inactive 152 tert-butyl (2-aminoethyl) Commerciallyavailable, carbamate CAS: 57260-73-8 153 4-bromo-2-methoxypyridineCommercially available, CAS: 100367-39-3 154 Route 3 and4-(piperidin-4-yl) pyridin- LCMS (Method I): m/z intermediates 2(1H)-onehydrochloride 179 (M + H)⁺ (ES+), at 28 and 153 2.57 min, UV active 155benzyl 4-(4,4,5,5-tetramethyl- Commercially available,1,3,2-dioxaborolan-2-yl)-3,6- CAS: 285961-15-7 dihydropyridine-1(2H)-carboxylate 158 isopropyl iodide Commercially available, CAS: 75-30-9157 Route 6 and methyl 2-{4-[(2S)-pyrrolidin- LCMS (Method J): m/zintermediates 2-yl]piperidin-1-yl}-6- 322 (M + H)⁺ (ES⁺), at 3 and 51azaspiro[3.4]octane-6- 4.37 min, UV inactive carboxylate•HCl 158Diethylamine Commercially available, CAS: 109-89-7 159 Route 13 andtert-butyl 4-[(2R)-2- LCMS (Method D): m/z intermediates(methoxycarbonyl)pyrrolidin- 313 (M + H—^(t)Bu)⁺ (ES⁺), 115 and 1501-yl]piperidine-1-carboxylate at 1.85 min, UV inactive 160 tert-butyl4-oxopiperidine-1- Commercially available, carboxylate CAS: 79099-07-3161 Ethyl 4-piperidinecarboxylate Commercially available, CAS: 1126-09-6162 Route 6 and ethyl 2-{4-[(2R)-pyrrolidin-2- LCMS (Method E): m/zintermediates yl]piperidin-1-yl}-6-azaspiro 336 (M + H)⁺ (ES+), at 2 and52 [3.4]octane-6-carboxylate 5.16 min, UV inactive 1634-bromo-1,3-thiazole Commercially available, CAS: 34259-99-9 164Intermediates 4-(1,3-thiazol-4-yl)piperidine ¹H NMR: (400 MHz, 155 and153 hydrobromide D₂O) δ: 1.82-2.10 (m, 2H), 2.15-2.44 (m 2H), 3.05-3.72(m, 5H), 7.72 (s, 1H), 9.62 (s, 1H), Two exchangeable protons notobserved 165 2-bromoethyl methyl ether Commercially available, CAS:6482-24-2 166 bromoacetonitrile Commercially available, CAS: 590-17-0167 methyl bromoacetate Commercially available, CAS: 96-32-2 168Methylamine solution Commercially available (2.0M in THF) CAS: 74-89-5169 2-chloropyrimidine Commercially available, CAS: 1722-12-9 170(1S,3S,5S)-Cyclohexane- Commercially available, 1,3,5-triol CAS:50409-12-6 171 phenylboronic acid Commercially available, CAS 93-80-6172 Intermediates (1R,5S)-3-phenyl-2,4-dioxa- ¹H NMR: (400 MHz, 170 and171 3-borabicyclo[3.3.1]nonan- CDCl₃) δ: 2.29 (d, J = 7-one 13.7 Hz, 1H), 2.47 (d, 7 = 12.8 Hz, 1 H), 2.63 (d, 7 = 16.2 Hz, 2 H), 2.95 (d, 7 =15.9 Hz, 2 H), 4.85 (br. s., 2 H), 7.30- 7.48 (m, 3 H), 7.73 (d, 7 = 7.0Hz, 2 H) 173 4-(1-propyl-1H-pyrazol-5- Commercially available,yl)piperidine CAS: 1342846-85-4 174 Intermediates4-[(2R)-4,4-difluoro-2- LCMS (Method C): m/z 126 and 150(methoxymethyl)pyrrolidin- 235 (M + H)⁺ (ES+), 1-yl]piperidinetrifluoroacetate at 1.02 min, UV inactive 175 4-chloropyrdineCommercially available, CAS: 626-61-9 176 2-bromopyridine Commerciallyavailable, CAS: 109-04-6 177 4-(1,4-dimethyl-1H-pyrazol- Commerciallyavailable, 3-yl) piperidine CAS: 1511937-89-5 1784-(1,4-dimethyl-1H-pysazol- Commercially available, 5-yl) piperidineCAS: 1540203-24-4 179 Intermediates 1-[(2R)-4,4-difluoro-1-(piperidin-LCMS (Method C): m/z 126 and 150 4-yl)pyrrolidin-2-yl]ethanol 235 (M +H)⁺ (ES+), at trifluoroacetate 0.79 min, UV inactive 1805-(pyrrolidin-2-yl)-1H- Commercially available, pyrazole dihydrochlorideCAS: 1361114-72-8 181 Route 9 and 4-[2-(1H-pyrazol-5-yl)pyrrolidin- LCMS(Method C): intermediates 1-yl]piperidine trifluoroacetate m/z 221 (M +H)⁺ 180 and 160 (ES+), at 0.87 min, UV active 1825-methylpyrrolidin-2-one Commercially available, CAS: 108-27-0 1834-iodopyridine Commercially available, CAS: 15354-87-2 184 Route 10 and5-methyl-1-(piperidin-4-yl) LCMS (Method C): m/z intermediatespyrrolidin-2-one acetate 183 (M + H)⁺ (ES+), at 182 and 183 0.53 min, UVactive 185 5,5-dimethylpyrrolidin-2-one Commercially available, CAS:5165-23-6 186 Route 10 and 5,5-dimethyl-1-(piperidin-4-yl) LCMS (MethodC): m/z intermediate pyrrolidin-2-one acetate 197 (M + H)⁺ (ES+), at 1850.78 min, UV active 187 (4S)-4-(propan-2-yl)-1,3- Commerciallyavailable, oxazolidin-2-one CAS: 17016-83-0 188 Route 10 and(4S)-3-(piperidin-4-yl)-4- LCMS (Method C): m/z intermediate(propan-2-yl)-1,3-oxazolidin- 213 (M + H)⁺ (ES+), at 187 2-one acetate0.74 min, UV active 189 methyl azepane-2-carboxylate Commerciallyavailable, CAS: 5228-33-1 190 Route 9 and methyl 1-(pipendin-4-yl) LCMS(Method C): m/z intermediate azepane-2-carboxylate 2.41 (M + H)⁺ (ES+),183 trifluoroacetate at 1.20, UV inactive 191 pyrrolidine-2,5-dioneCommercially available, CAS: 123-56-8 192 tert-butyl 4-hydroxy-Commercially available, piperidine-1-carboxylate CAS: 109384-19-2 1931-(piperidin-4-yl)pyrrolidine- LCMS (Method C): m/z 2,5-dionetrifluoroacetate 183 (M + H)⁺ (ES+), at 0.29 min, UV inactive 194tert-butyl 4-cyanopiperidine- Commercially available, 1-carboxylate CAS:91419-52-2 195 Route 15 and 4-(1-methyl-1H-tetrazol- LCMS (Method K):m/z intermediates 5-yl)piperidine hydrochloride 168 (M + H)⁺ (ES+), at130 and 134 2.41 min, UV inactive 196 (4R)-4-(propan-2-yl)-1,3-Commercially available, oxazolidin-2-one CAS: 9553G-58-8 197 Route 10and (4R)-3-(piperidin-4-yl)-4- LCMS (Method C): m/z intermediate(propan-2-yl)-1,3-oxazolidin- 213 (M + H)⁺ (ES+), at 193 2-one acetate0.78 min, UV active 198 (5S)-5-(hydroxymethyl) Commercially available,pyrrolidin-2-one CAS: 17342-08-4 199 Route 11 and(5R)-5-methyl-1-(piperidin- LCMS (Method C): m/z intermediate4-yl)pyrrolidin-2-one acetate 183 (M + H)⁺ (ES+), 198 at 0.53 mm, UVactive 200 Route 11 and (5R)-5-ethyl-1-(piperidin-4-yl) LCMS (Method C):m/z intermediate pyrrolidin-2-one acetate 197 (M + H)⁺ (ES+), 198 at0.69 min, UV active 201 (5R)-5-(hydroxymethyl) Commercially available,pyrrolidin-2-one CAS: 66673-40-3 202 Route 11 and(5S)-5-methyl-1-(piperidin-4- LCMS (Method C): m/z intermediateyl)pyrrolidin-2-one acetate 183 (M + H)⁺ (ES+), at 201 0.54 min, weaklyUV active 203 Route 11 and (5S)-5-ethyl-1-(piperidin-4-yl) LCMS (MethodC): m/z intermediate pyrrolidin-2-one acetate 197 (M + H)⁺ (ES+), at 2010.69 min, UV active 204 (2R)-2-aminopropan-1-ol Commercially available,CAS: 35320-23-1 205 Route 12 and (4R)-4-methyl-3-(piperidin-4- LCMS(Method C): m/z intermediate yl)-1,3-oxazolidin-2-one 185 (M + H)⁺(ES+), at 204 acetate 0.37 min, UV active 206 (2R)-2-aminobutan-1-olCommercially available, CAS; 5856-63-3 207 Route 12 and(4R)-4-ethyl-3-(piperidin-4- LCMS (Method C): m/z intermediateyl)-1,3-oxazolidin-2-one acetate 199 (M + H)⁺ (ES+), at 208 0.59 min, UVactive 208 (2S)-2-aminopropan-1-ol Commercially available, CAS:2749-11-3 209 Route 12 and (4S)-4-methyl-3-(piperidin-4- LCMS (MethodC): m/z intermediate yl)-1,3-oxazolidin-2-one 185 (M + H)⁺ (ES+), at 208acetate 0.39 min, UV active 210 (2S)-2-aminobutan-1-ol Commerciallyavailable, CAS: 5856-62-2 211 Route 12 and (4S)-4-ethyl-3-(piperidin-4-LCMS (Method C): m/z intermediate yl)-1,3-oxazolidin-2-one acetate 199(M + H)⁺ (ES+), at 210 0.60 min, UV active 2121-methylimidezolidin-2-one Commercially available, CAS: 694-32-6 213Route 12 and 1-methyl-3-(piperidin-4-yl) LCMS (Method C): m/zintermediate imidazolidin-2-one acetate 184 (M + H)⁺ (ES+), at 212 0.40min, UV active 214 tert-butyl 4-aminopiperidine- Commercially available,1-carboxylate CAS: 87120-72-7 215 Intermediate4-(1H-tetrazol-1-yl)piperidine LCMS (Method K): m/z 214 hydrochloride154 (M + H)⁺ (ES+), at 2.22 min, weakly UV active 2161-(tert-butoxycarbonyl) Commercially available, piperidine-4-carboxylicacid CAS: 84358-13-4 217 cyclopropanamine Commercially available, CAS:765-30-0 218 Intermediates 4-(1-cyclopropyl-1H-tetrazol- LCMS (MethodF): m/z 216 and 217 5-yl)piperidine hydrochloride 194 (M + H)⁺ (ES+), at0.46 min, weakly UV active 219 1-ethyl-4-methyl-1H-pyrazol- Commerciallyavailable, 5-amine CAS: 3702-13-4 220 Route 1 and4-(1-ethyl-4-methyl-1H- LCMS (Method I): m/z intermediatespyrazol-5-yl)piperidine 194 (M + H)⁺ (ES+), at 28 and 252 hydrochloride3.13 min, UV active 221 R-pipecolinic acid Commercially available, CAS:1723-00-8 222 propylphosphonic anhydride Commercially available,solution ≥50 wt. % in ethyl CAS: 68957-94-8 acetate 223 Route 16 and(R)-N-methyl-[1,4′- ¹H-NMR (400 MHz, intermediatesbipiperidine]-2-carboxamide DMSO) δ: 1.75-1.91 160, 221 (m, 4H),2.21-2.29 (m, and 222 4H), 2.69 (d, J = 4.8 Hz, 3H), 2.94-3.07 (m, 3H),3.30-3.49 (m, 4H), 3.62- 3.80 (m, 2H), 4.10-4.12 (m, 1H), 9.03 (br. s.,1H), 10.01 (br. s., 1H). 224 S-pipecolinic acid Commercially available,CAS: 3105-95-1 225 Route 16 and (S)-N-methyl-[1,4′- ¹H-NMR (400 MHz:intermediates bipiperidine]-2-carboxamide CDCl₃) δ: 1.25-1.40 (m, 180,221 2H), 1.55-1.69 (m, 4H), and 224 1.82-2.10 (m, 4H), 2.32- 2.38 (m,1H), 2.51-2.65 (m, 3H), 2.79-2.85 (m, 1H), 2.82 (d, J = 4.8 Hz. 3H),3.12-3.19 (m, 3H), 6 75 (br. s., 1H) 226 Z-β-ala-OH Commerciallyavailable, CAS: 2304-94-1 227 2-bromopyridine Commercially available,CAS: 103-04-6 228 Cbz-OSu Commercially available, CAS: 13139-17-8 229Intermediates ethyl 2-([2,4′-bipiperidin]- ¹H-MMR (400 MHz; 160, 2271′-yl)-6-azaspiro[3.4] CDCl₃) δ: 1.22 (t, J = and 228octane-6-carboxylate 6.8 Hz, 3H), 1.32- 1.49 (m, 4H), 1.60- 2.90 (m,12H), 2.08 (bs, 1H), 2.51-2.75 (m, 4H), 2.91-2.98 (m, 3H), 3.25-3.50 (m,6H), 4.12 (q, J = 3.3 Hz, 2H). 230 propionic acid Commerciallyavailable, CAS: 79-09-4 231 2-bromo ethyl methyl ether Commerciallyavailable, CAS: 6482-24-2 232 benzyl bromide Commercially available,CAS: 202-847-3 233 methyl bromo acetate Commercially available, CAS:96-32-2 234 1,1′-carbonyldiimidazole Commercially available, CAS:530-62-1 235 tert-butyl (2-hydroxyethyl) Commercially available,methylcarbamate CAS: 57561-39-4 236 1,1,1-trifluoro-3-iodopropaneCommercially available, CAS: 460-37-7 237 2,2,2-trifluoroethylCommercially available, trifluoromethanesulfonate CAS: 6226-25-1 2382-chloro-N,N-dimethyl- Commercially available, acetamide CAS: 2375-89-0239 methyl isothiocyanate Commercially available, CAS: 556-61-8 240isoindoline-1-carboxylic Commercially available, acid hydrochloride CAS:96016-96-5 241 trimethylphosphonoacetate Commercially available, CAS:5927-18-4 242 methyl cyanoacetate Commercially available, CAS: 105-34-0243 Intermediates tert-butyl 1-(piperidin-4- ¹H-NMR (400 MHz, 240, 241yl)isoindoline-2-carboxylate CDCl₃) δ: 1.42 and 242 (s, 9H), 1.51-1.62(m, 3H), 3.15-3.18 (m, 2H), 3.37-3.42 (m, 4H), 4.08-4.11 (m, 1H),4.32-4.38 (m, 2H), 7.18-7.34 (m, 4H). 244 1-iodo-2-fluoroethaneCommercially available, CAS: 762-51-3 245 tert-butyl 4-hydroxypipendine-Commercially available, 1-carboxylate CAS: 109384-19-2 2461H-1,2,3-triazole Commercially available, CAS: 283-35-8 247Intermediates 4-(2H-1,2,3-triazol-2-yl) LCMS (Method K): m/z 245 and 246piperidine hydrochloride 153 (M + H)⁺ (ES+), at 2.94 min, UV active 2481-ethyl-4-methyl-1H Commercially available, pyrazole amine CAS:354795-57-6 249 isoamyl nitrite Commercially available, CAS: 110-45-3250 Route 17 and 4-ethyl-5-iodo-1-methyl- LCMS (Method I): m/zintermediates 1H-pyrazole 236 (M + H)⁺ (ES+), at 248 and 249 4.36 min,UV active 251 Route 1 and 4-(1-ethyl-4-methyl-1H- LCMS (Method I): m/zintermediates pyrazol-5-yl)piperidine 194 (M + H)⁺ (ES+), at 3.37 min,28 and 250 hydrochloride UV active 252 Route 17 and 4-methyl-5-iodo-1-LCMS (Method I): m/z intermediates ethyl-1H-pyrazole 236 (M + H)⁺ (ES+),at 4.40 min, 219 and 249 UV active 253 tert-butyl 4-bromo- Commerciallyavailable, piperidine-1-carboxylate CAS: 160695-79-8 2545-methyl-2H-tetrazole Commercially available, CAS: 4076-36-2 255Intermediates 4-(5-methyl-1H-tetrazol- ¹H-NMR: (400 MHz, 253 and 2541-yl)piperidine DMSO) δ: 2.15-2.29 hydrochloride (m, 4H), 2.56 (s, 3H),3.08 (d, J = 10.2 Hz, 2H), 3.42 (d. J = 12.6 Hz 2H), 4.74-4.87 (m, 1H),6.33-6.38 (m, 1H). 256 2-bromo-1,3,4-thiadiazole Commercially available,CAS: 61929-24-6 257 1-(tert-butyl) 2-methyl (R)- Commercially available,4,4-difluoropyrrolidine- CAS: 647857-74-7 1,2-dicarboxylate 258Intermediates (R)-2-(4,4-difluoro-1- ¹H-NMR: (400 MHz, 160 and 257(piperidin-4-yl)pyrrolidin- CDCl₃) δ: 1.11 (s, 3H), 1.21 (s, 3H),2-yl)propan-2-ol 1.21-1.31 (m, 1H), 1.49-1.52 (m, hydrochloride 2H),1.71-1.89 (m, 2H), 2.19-2.30 (m, 2H), 2.50-2.83 (m, 3H), 3.02- 3.43 (m,4H). N—H and O—H not observed. 259 (R)-Methyl 4,4-difluoro- Commerciallyavailable, pyrrolidine-2-carboxylale CAS: 1408057-39-5 HCl 260 Route 14and tert-butyl 4-[(2R)-4,4- LCMS (Method D): m/z 349 intermediatesdifluoro-2-(methoxy- (M + H)⁺ (ES+) at 2.03 160 and 259 carbonyl)pyrrolidin-1- min, UV inactive yl]piperidine-1-carboxylate 261(S)-Methyl 4,4-difluoro- Commercially available,pyrrolidine-2-carboxylate CAS: 158046-05-8 HCl 262 Route 14 andtert-butyl 4-[(2S)-4,4- LCMS (Method D) m/z 349 intermediatesdifluoro-2-(methoxy- (M + H)⁺ (ES+) at 2.04 min, 160 and 261carbonyl)pyrrolidin-1-yl] UV inactive piperidine-1-carboxylate 263(R)-(−)-3-Fluoropyrrolidine•HCl Commercially available CAS: 138725-55-8264 (S)-(+)-3-Fluoropyrrolidine•HCl Commercially available CAS:136725-53-6 265 4,4-difluoropiperidine•HCl Commercially available CAS:144230-52-4 266 Route 14 and tert-butyl 4,4-difluoro-1,4′- LCMS (MethodD): m/z 305 intermediates bipiperidine-1′-carboxylate (M + H)⁺ (ES+) at1.97 min, 160 and 265 UV inactive 267 Thiomorpholine Commerciallyavailable CAS: 123-90-0 268 Route 13 and tert-butyl 4-(thiomorpholin-4-LCMS (Method D): m/z intermediates yl)piperidine-1-carboxylate 287 (M +H)⁺ (ES+) at 1.86 min, 160 and 267 UV inactive 269 1-piperidin-4-ylpyrolidin-2-one Commercially available, CAS: 91596-61-1 2703,3-difluoro-4-piperidine•HCl Commercially available CAS: 496807-97-7271 Route 14 and tert-butyl 3,3-difluoro-1,4′- LCMS (Method D): m/z 305intermediates bipiperidine-1′-carboxylate (M + H)⁺ (ES+) at 1.54 min,160 and 279 UV inactive 272 Route 13 and tert-butyl 4-(morpholin-4-yl)LCMS (Method D): m/z 271 intermediates pipendine-1-carboxylate (M + H)⁺(ES+) at 1.54 min, 80 and 160 UV inactive 273 2-(R)-2 Trifluoro-Commercially available methylpyrrolidine CAS: 1073556-31-6 274 Route 13and tert-butyl 4-[(2R)-2-(tri- LCMS (Method D): m/z 267 intermediatesfluoromethyl)pyrrolidin-1-yl] (M + H)⁺ (ES+) at 2.27 and 160 and 273piperidine-1-carboxylate 2.30 min, UV inactive 275 piperidineCommercially available CAS:110-89-4 276 Route 13 and tert-butyl1,4′-bipiperidine- LCMS (Method D): m/z 269 intermediates 1′-carboxylate(M + H)⁺ (ES+) at 2.05 min, 180 and 275 UV inactive 277 2-(S)-2Trifluoromethyl- Commercially available pyrrolidine CAS: 119580-41-5 278Route 13 and tert-butyl 4-[(2S)-2-(tri- LCMS (Method D): m/z 323intermediates fluoromethyl)pyrrolidin-1- (M + H)⁺ (ES+) at 2.27 min, 160and 277 yl]piperidine-1-carboxylate UV inactive 279 3-azabicyclo[3.1.0]Commercially available hexane•HCl CAS: 73799-84-1 280 Route 14 andtert-butyl 4-(3-azabicyclo LCMS (Method D): m/z 267 intermediates[3.1.0]hex-3-yl)piperdine- (M + H)⁺ (ES+) at 2.24 min, 180 and 2791-carboxylate UV inactive 281 (R)-1-(tert-Butoxy- Commercially availablecarbonyl)piperidine-2- CAS: 23697-17-8 carboxylic acid 282 Intermediatetert-butyl (2R)-2-(dimethyl- ¹H NMR: (400 MHz, DMSO-d6) 281carbamoyl)piperidine-1- δ: 1.22-1.42 (m, 12 H), 1.46- carboxylate 1.83(m, 4 H), 2.79 (s, 3 H), 2.95 (s, 3 H), 3.70 (d, J = 12.5 Hz, 1 H).4.74-4.94 (m, 1 H) 283 Route 14 and tert-butyl (2R)-2-(dimethyl- LCMS(Method D): m/z 340 intermediates carbamoyl)-1,4′-bipiperidine- (M + H)⁺(ES+) at 1.39 min, 180 and 282 1′-carboxylate UV inactive 284(S)-3-Boc-thiazolidine-4- Commercially available carboxylic acid CAS:63091-82-7 285 Intermediate 3-tert-butyl 4-methyl (4S)- ¹H NMR: (400MHz, 284 1,3-thiazolidine-3,4- CDCl₃) δ: 1.47 (s, 5 H), dicarboxylate1.43 (s, 4 H), 3.13-3.22 (m, 1 H), 3.22-3.37 (m, 1 H), 3.75 (s, 3 H),4.34- 4.52 (m, 1 H), 4.57-4.60 (m, 0.5 H), 4.61-4.70 (m, 1H). 4.84-4.92(m, 0.5 H) 286 Route 14 and tert-butyl 4-[(4S)-4- LCMS (Method D): m/zintermediates (methoxycarbonyl)-1,3- 331 (M + H)⁺ (ES+) at 2.16 160 and284 thiazolidin-3-yl] min, UV inactive piperidine-1-carboxylate 2875-(Pyrrolidin-2-yl)-1H- Commercially available 1,2,3,4-tetrazole CAS:758710-03-1 288 Route 13 and tert-butyl 4-[2-(2H- LCMS (Method D): m/zintermediates tetrazol-5-yl)pyrrolidin- 323 (M + H)⁺ (ES+) at 1.90 min,160 and 287 1-yl]piperidine-1- UV inactive carboxylate 289(R)-2-Pipendinecarboxylic Commercially available acid methyl ester CAS:18650-38-9 hydrochloride 290 Route 14 and 1-tert-butyl 2-methyl LCMS(Method C): m/z 327 intermediates (2R)-1,4-bipiperidine- (M + H)⁺ (ES+)at 1.43 min, 160 and 289 1′,2-dicarboxylate UV inactive 291(2R,4R)-4-Hydroxy- Commercially available pyrrolidine-1,2-di- CAS:114676-89-6 carboxylic acid 1-tert- butyl ester 2-methyl ester 292D-proline, 2-methyl-, Commercially available methyl ester, hydrochlorideCAS: 1286768-32-8 (1:1) 293 Route 14 and tert-butyl 4-[(2R)-2- LCMS(Method D): m/z 271 intermediates (methoxycarbonyl)-2- (M + H)⁺ (ES+) at2.35 min, 160 and 292 methylpyrrolidin-1-yl] UV inactivepiperidine-1-carboxylate 294 (2R)-(+)-1-Boc-2- Commercially availablepyrrolidinemethanol CAS: 83436-58-9 295 Intermediate tert-butyl (2R)-2-¹H NMR: (400 MHz, 294 (fluoromethyl)pyrrolidine- CDCl₃) δ: 1.46 (s, 5H), 1-carboxylate 1.57 (s, 4 H), 1.80-2.00 (m, 2 H), 2.01-2.15 (m, 2 H),3.09-3.23 (m, 1 H), 3.65 (dt, J = 11.4, 7.8 Hz, 1 H), 3.80-3.96 (m, 1H). 4.17 (dd, J = 8.8, 3.3 Hz, 1 H), 4.51 (t, J = 8.4 Hz, 1H) 296 Route14 and tert-butyl 4-[(2R)-2- LCMS (Method D): m/z intermediates(fluoromethyl) 287 (M + H)⁺ (ES+) at 2.56 160 and 295 pyrrolidin-1-yl]min, UV inactive piperidine-1-carboxylate 297 Intermediate tert-butyl(2R)-2- ¹H NMR: (400 MHz, CDCl₃) 294 (difluoromethyl) δ: 1.36-1.45 (m, 1H), 1.47 pyrrolidine-1-carboxylate (S, 3 H), 1.57 (s, 6 H), 3.16 (dt, J= 11.0, 6.8 Hz, 1 H), 3.22-3.32 (m, 1 H), 3.34- 3.54 (m, 1 H) 3.59-3.73(m, 2 H), 3.77-3.99 (m, 1 H), 4.12-4.29 (m, 1 H) 298 Route 14 andtert-butyl 4-[(2R)-2- LCMS (Method D): m/z 305 intermediates(difluoromethyl) (M + H)⁺ (ES+) at 2.80 min, 160 and 297pyrrolidin-1-yl] UV inactive piperidine-1-carboxylate 2997-Oxa-1-azaspiro[4.4] Commercially available nonan-6-one•HCl CAS:1018670-73-9 300 Route 14 and tert-butyl 4-(6-oxo-7-oxa- LCMS (MethodD): m/z 325 intermediates 1-azaspiro[4.4]non-1-yl) (M + H)⁺ (ES+) at2.08 min, 160 and 299 piperidine-1-carboxylate UV inactive 3014-Nitrophenyl Commercially available chloroformate CAS: 7593-46-1 302Route 18 and 4-nitrophenyl 2-[4-(1H- LCMS (Method D): m/z 425intermediates pyrazol-1-yl)piperidin- (M + H)⁺ (ES+) at 2.12 min, 1, 32and 301 1-yl]-6-azaspiro[3,4] UV active octane-6-carboxylate 303Ethanol-1,1,2,2,2-d₅ Commercially available CAS: 1859-08-1 304Ethanol-1,1-d₂ Commercially available CAS: 1859-09-2 305Ethanol-2,2,2-d₃ Commercially available CAS: 1759-87-1 306 Route 18 and4-nitrophenyl 2[4-(1- LCMS (Method D): m/z 440 intermediatesmethyl-1H-pyrazol-5- (M + H)⁺ (ES+) at 2.11 min, 1, 9 and 301yl)piperidin-1-yl]-6- UV active azaspiro[3.4]octane- 6-carboxylate 307Dimethylamine hydrochloride Commercially available CAS: 506-59-2 308Route 16 and Mixture of tert-butyl 4- LCMS (Method D): m/z 337intermediates [2-(1-methyl-1H-tetrazol-5- (M + H)⁺ (ES+) at 2.43 min,130 and 288 yl)pyrrolidin-1-yl]piperidine- UV inactive 1-carboxylate andtert-butyl 4- [2[(2-methyl-2H-tetrazol-5- yl)pyrrolidin-1-yl]piperidine-1-carboxylate 309 1-tert-butyl 2-methyl Commercially available(2R,4R)-4-fluoro- CAS 647857-43-0 pyrrolidine-1,2-dicarboxylate 3101-tert-butyl 2-methyl (2R, Commercially available4R)-4-fluoropyrrolidine- CAS 647857-39-4 1,2-dicarboxyate 311 Route 14and tert-butyl 4-[(2R,4R)-4- LCMS (Method D): m/z 331 intermediatesfluoro-2-(methoxycarbonyl) (M + H)⁺ (ES+) at 1.93 min, 160 and 303pyrrolidin-1-yl]piperidine- UV inactive 1-carboxylate 312 Route 14 andtert-butyl 4-[(2R,4S)-4- LCMS (Method D): m/z 331 intermediatesfluoro-2-(methoxycarbonyl) (M + H)⁺ (ES+) at 2.04 min, 180 and 310pyrrolidin-1-yl]piperidine- UV inactive 1-carboxylate 313(R)-2-(pyrrolidin-2-yl)thiazole Commercially available CAS: 1228558-20-0314 Route 9 and 4-[(2R)-2-(1,3-thiazol-2-yl) LCMS (Method K): m/z 238intermediates pyrrolidin-1-yl]piperidine (M + H)⁺ (ES+) at 7.00 min, 160and 313 dihydrochloride UV active 315 (2R)-2-(thiophen-2-yl]Commercially available pyrrolidine CAS: 154777-22-7 316 Route 3 and4-[(2R)-2-(thiophen-2- LCMS (Method K): m/z 237 intermediatesyl)pyrrolidin-1-yl] (M + H)⁺ (ES+) at 7.80 min, 160 and 315 piperidinedihydrochloride UV active 317 3-[(2R)-pyrrolidin-2-yl]- Commerciallyavailable 1,2-oxazole CAS: 1255147-67-1 318 Route 9 and4-[2-(1,2-oxazol-3-yl) LCMS (Method K): m/z 222 intermediatespyrrolidin-1-yl]piperidine (M + H)⁺ (ES+) at 8.24 min, 160 and 317dihydrochloride UV active 319 Route 15 and 4-(2-ethyl-2H-tetrazol-5-LCMS (Method I): m/z (M + H)⁺ intermediates yl)piperidine hydrochloride(ES+) at 3.128 min, UV active 114 and 194 320 Route 15 and4-(1-ethyl-1H-tetrazol-5- LCMS (Method I): m/z 182 intermediatesyl)piperidine hydrochloride (M + H)⁺ (ES+) at 2.54 min, 114 and 194 UVactive 321 6,7-dihydro-5H-pyrrolo[3: Commercially available 4-b]pyridinedihydrochloride CAS: 147740-02-1 322 6-Bromohexanoyl chlorideCommercially available CAS: 22809-37-6 323 Route 6 and Mthyl2-[4-(pyrrolidin-2-yl) LCMS (Method J): m/z intermediatespiperidin-1-yl]-6-azaspiro 322 (M + H)⁺ (ES+), at 3 and 53[3.4]octane-6-carboxylate•HCl 4.37 min, UV inactive

TABLE 3 Ex. Synthetic LCMS No. Name Intermediate method 1H NMR MethodLCMS data 1-1 Isomer 2: ethyl 2-[4-(1H- 2 and 5 a (400 MHz, DMSO-d₅) δ:1.14 (t, J = 6.6 Hz, 3H), B m/z 333 (M + H)⁺ imidazol-2-yl)piperidin-1-1.60-1.86 (m, 11H), 1.95-2.02 (m, 2H), 2.60-2.66 (ES+), at 2.69 min,yl]-6-azaspiro[3.4]octane- (m, 1H), 2.76-2.84 (m, 2H), 3.10-3.28 (m,4H), UV inactive 6-carboxylate 3.98 (q, J = 6.6 Hz, 2H), 6.78-6.83 (m,2H), NH not observed 1-2 Isomer 2: ethyl 2-[4-(4- 2 and 22 as (400 MHz,CDCl₃) δ: 1.24 (t, J = 7.0 Hz, 3H), C m/z 367/369 (M +chloro-1H-imidazol-2- 1.81-2.23 (m, 12H), 2.77-2.97 (m, 2H), 2.97-3.15H)⁺ (ES+), at 1.57 yl)piperidin-yl]-6- (m, 2H), 3.28-3.35 (m, 2H),3.35-3.46 (m, 2H), min, UV active azaspiro[3.4]octane-6- 4.11 (q, J =7.0 Hz, 2H), 6.82 (s, 1H), NH not carboxylate observed 1-3 Isomer 2:ethyl 2-{4-[4- 2 and 33 b (400 MHz, DMSO-d₅) δ: 1.18 (t, J = 7.0 Hz,3H), G m/z 401 (M + H)⁺ (trifluoromethyl)-1H- 1.60-1.73 (m, 2H),1.73-1.93 (m, 8H), 1.97-2.06 (ES+), at 5.42 min,imidazol-2-yl]piperidin-1- (m, 2H), 2.61-2.73 (m, 2H), 2.78-2.87 (m,2H), UV active yl}-6-azaspiro[3.4]octane- 3.14-3.20 (m, 2H), 3.26-3.33(m, 2H), 4.01 (q, J = 6-carboxylate 7.0 Hz, 2H), 7.64 (s, 1H), NH notobserved. 1-4 Isomer 2: ethyl 2-[4-(4- Example c (400 MHz, DMSO-d₅) δ:1.17 (t, J = 7.0 Hz, 3H), G m/z 358 (M + H)⁺ cyano-1H-imidazol-2- 1-31.58-1.71 (m, 2H), 1.73-1.92 (m, 8H), 1.95-2.05 (ES+), at 4.71 min,yl)piperidin-1-y]-6- (m, 2H), 2.62-2.73 (m, 2H), 2.76-2.87 (m, 2H), UVactive azaspiro[3.4]octane-6- 3.13-3.19 (m, 2H), 3.25-3.32 (m, 2H), 4.00(q, J = carboxylate 7.0 Hz, 2H), 8.02 (s, 1H), 12.66 (br, 1H). 1-5Isomer 2: ethyl 2-[4-(4,5- 2 and 25 as (400 MHz, CD₃OD) δ: 1.20-1.31 (m,3H), 1.67- C m/z 401/403/405 dichloro-1H-imidazol-2- 1.82 (m, 2H),1.87-2.02 (m, 8H), 2.10-2.18 (m, (M + H)⁺ (ES+), atyl)piperidin-1-yl]-6- 2H), 2.61-2.72 (m, 1H), 2.76-2.88 (m, 1H), 2.90-1.57 min, UV azaspiro[3.4]octane-6- 3.04 (m, 2H), 3.25-3.29 (m, 2H),3.36-3.46 (m, active carboxylate 2H), 4.10 (q, J = 7.0 Hz, 2H), NH notobserved 1-6 Isomer 2: methyl 2-[4-(1- 3 and 15 at (400 MHz, CDCl₃) δ:1.81-2.10 (m, 11H), 2.17- B m/z 333 (M + H)⁺ methyl-1H-imidazol-2- 2.53(m, 1H), 2.57-2.79 (m, 2H), 2.87-3.05 (m, (ES+), at 2.78 min,yl)piperidin-1-yl]-6- 2H), 3.19-3.47 (m, 4H), 3.59 (s, 3H), 3.68 (s,3H), UV inactive azaspiro[3.4]octane-6- 6.77 (s, 1H), 6.93 (s, 1H).carboxylate 1-7 Isomer 2: ethyl 2-[4-(1- 1 and 6 d (300 MHz, CDCl₃) δ:1.22 (t, J = 7.0 Hz, 3H), B m/z 347 (M + H)⁺ methyl-1H-imidzol-2-1.76-2.09 (m, 12H), 2.54-2.78 (m, 2H), 2.92-2.96 (ES+), at 3.07 min,yl)piperidin-1-yl]-6- (m, 2H), 3.19-3.29 (m, 2H), 3.37 (dt, J = 13.6,6.6 UV inactive azaspiro[3.4]octane-6- Hz, 2H), 3.57 (s, 3H), 4.08 (q, J= 7.0 Hz, 2H), carboxylate 6.74 (s, 1H), 6.90 (s, 1H). 1-8 Isomer 2:ethyl 2-{4-[1- 1 and 5 d (400 MHz, CDCl₃) δ: 1.24 (t, J = 7.5 Hz, 3H),1.42 B m/z 405 (M + H)⁺ (ethoxycarbonyl)-1H- (t, J = 7.0 Hz, 3H),1.74-2.15 (m, 12H), 2.70-2.76 (ES+), at 3.94 min,imidazol-2-yl]piperidin-1- (m, 1H), 2.93-2.99 (m, 2H), 3.15-3.49 (m,5H), weakly UV active yl}-6-azaspiro[3.4]octane- 4.11 (q, J = 7.0 Hz,2H), 4.42 (q, J = 7.5 Hz, 2H), 6-carboxylate 6.89 (s, 1H), 7.35 (s. 1H)1-9 Isomer 2: methyl 2-[4- 3 and 34 b and e 400 MHz, DMSO-d₅) δ:1.60-1.85 (m, 10H), 1.99- G m/z 347 (M + H)⁺ (1,5-dimethyl-1H- 2.08 (m,2H), 2.11 (d, J = 1 Hz, 3H), 2.60-2.71 (m, (ES+), at 4.83 min,imidazol-2-yl)piperidin-1- 2H), 2.79-2.88 (m, 2H), 3.21-3.28 (m, 2H),3.28- UV active yl]-6-azaspiro[3.4]octane- 3.32 (m, 2H), 3.41 (s, 3H),3.58 (s, 3H), 6.49 (s, 6-carboxylate 1H) 1-10 Isomer 2: ethyl 2-[4-(1,5-2 and 34 b and e (400 MHz, CD₃OD) δ: 1.22-1.36 (m, 3H), 1.82- G m/z 361(M + H)⁺ dimethyl-1H-imidazol-2- 2.10 (m, 10H), 2.12-2.27 (m, 2H), 2.20(s, 3H), (ES+), at 5.55 min, yl)piperidin-1-yl]-6- 2.76-2.97 (m, 2H),2.99-3.12 (m, 2H), 3.25-3.47 UV active azaspiro[3.4]octane-6- (m, 4H),3.53 (s, 3H), 4.12 (q, J = 7.1 Hz, 211), carboxylate 0.61 (s, 1H) 1-11Isomer 2: methyl 2-[4- 3 and 36 b and e (400 MHz, DMSO-d₅) δ: 1.57-1.93(m, 10H), G m/z 347 (M + H)⁺ (1,4-dimethyl-1H- 1.96-2.06 (m, 2H), 2.02(s, 3H), 2.59-2.79 (m, (ES+), at 4.54 min, imidazol-2-yl)piperidin-1-2H), 2.81-2.92 (m, 2H), 3.15-3.22 (m, 2H), 3.26- UV activeyl]-6-azaspiro[3.4]octane- 3.33 (m, 2H), 3.50 (s, 3H), 3.57 (s, 3H),6.66 (s, 6-carboxylate 1H) 1-12 Isomer 2: ethyl 2-[4-(1,4- 2 and 36 band e (400 MHz, DMSO-d₅) δ: 1.18 (t, J = 7.0 Hz, 3H), G m/z 361 (M + H)⁺dimethyl-1H-imidazol-2- 1.59-1.91 (m, 10H), 1.98-2.05 (m, 2H), 2.02 (s,(ES+), at 5.34 min, yl)piperidin-1-yl]-6- 3H), 2.67-2.75 (m, 2H),2.82-2.90 (m, 2H), 3.16- UV active azaspiro[3.4]octane-6- 3.22 (m, 2H),3.27-3.32 (m, 2H), 3.49 (s, 3H), 4.01 carboxylate (q, J = 7.0 Hz, 2H),6.66 (s, 1H) 1-13 Isomer 2: methyl 2-[4-(5- 3 and 20 as (400 MHz, CDCl₃)δ: 1.81-2.01 (m, 10H), 2.01- C m/z 367/369 (M + chloro-1-methyl-1H- 2.11(m, 2H), 2.55-2.66 (m, 1H), 2.66-2.79 (m, H)⁺ (ES+), at 1.61imidazol-2-yl)piperidin-1- 1H), 2.91-3.00 (m, 2H), 3.25 (s, 1H), 3.32(s, 1H), min, UV active yl]-6-azaspiro[3.4]octane- ), 3.34-3.40 (m, 1H),3.41-3.46 (m, 1H), 3.52 (s, 6-carboxylate 3H), 3.68 (s, 3H), 6.86 (s,1H) 1-14 Isomer 2: ethyl 2-[4-(5- 2 and 20 as (400 MHz, CDCl₃) δ: 1.25(t, J = 7.0 Hz, 3H), C m/z 381/383 (M + chloro-1-methyl-1H- 1.81-2.01(m, 10H), 2.01-2.11 (m, 2H), 2.55-2.66 H)⁺ (ES+), at 1.69imidazol-2-yl)piperidin-1- (m, 1H), 2.66-2.78 (m, 1H), 2.90-3.00 (m,2H), min, UV active yl]-6-azaspiro[3.4]octane- 3.26 (s, 1H), 3.31 (s,1H), ), 3.34-3.47 (m, 2H), 6-carboxylate 3.52 (s, 3H), 4.12 (q, J = 7.0Hz, 2H), 6.86 (s, 1H) 1-15 Isomer 2: ethyl 2-{4-[1- 2 and 37 b (400 MHz,DMSO-d₅) δ: 1.18 (t, J = 7.0 Hz, 3H), G m/z 415 (M + H)⁺ methyl-4-1.58-1.72 (m, 2H), 1.73-1.93 (m, 8H), 1.95-2.08 (ES+), at 4.95 min,(trifluoromethyl)-1H- (m, 2H), 2.65-2.81 (m, 2H), 2.82-2.92 (m, 2H), UVactive imidazol-2-yl]piperidin- 3.14-3.23 (m, 2H), 3.25-3.34 (m, 2H),3.65 (s, 1-yl}-6- 3H), 4.02 (q, J = 7.0 Hz, 2H), 7.67 (s, 1H)azaspiro[3.4]octane- 6-carboxylate 1-16 Isomer 2: methyl 2-[4- 3 and 21as (400 MHz, CDCl₃) δ: 1.79-2.00 (m, 10H), 2.00- C m/z 401/403/405(4,5-dichloro-1-methyl- 2.11 (m, 2H), 2.56-2.66 (m, 1H), 2.67-2.76 (m,(M + H)⁺ (ES+), at 1H-imidazol-2- 1H) 2.89-3.00 (m, 2H), 3.25 (s, 1H),3.31 (s, 1H), 1.70 min, UV yl)piperidin-1-yl]-6- ), 3.33-3.40 (m, 1H),3.41-3.46 (m, 1H), 3.53 (s, active azaspiro[3.4]octane-6- 3H), 3.69 (s,3H) carboxylate 1-17 Isomer 2: ethyl 2-[4-(4,5- 2 and 21 as (400 MHz,CDCl₃) δ: 1.25 (t, J = 7.0 Hz, 3H), C m/z 415/417/419dicloro-1-methyl-1H- 1.79-2.00 (m, 10H), 2.01-2.10 (m, 2H), 2.55-2.66(M + H)⁺ (ES+), imidazol-2-yl)piperidin-1- (m, 1H), 2.66-2.79 (m, 1H),2.90-2.99 (m, 2H), at 1.79 min, yl]-6-azaspiro[3.4]octane- 3.26 (s, 1H),3.31 (s, 1H), ), 3.34-3.47 (m, 2H), UVactive 6-carboxylate 3.53 (s, 3H),4.12 (q, J = 7.0 Hz, 2H) 1-18 Isomer 2: ethyl 2-[4-(1H- 2 and 7 a (400MHz, CDCl₃) δ: 1.24 (t, J = 7.0 Hz, 3H), B m/z 333 (M + H)⁺pyrazol-5-yl)piperidin-1- 1.68-2.13 (m, 12H), 2.69-2.75 (m, 2H),2.91-2.98 (ES+), at 3.16 min, yl]-6-azaspiro[3.4]octane- (m, 2H),3.18-3.52 (m, 4H), 4.11 (q, J = 7.0 Hz, UV inactive 6-carboxylate 2H),6.11 (s, 1H), 7.48 (s, 1H), NH not observed 1-19 Isomer 2: ethyl2-[4-(3- 2 and 8 a (400 MHz, CDCl₃) δ: 1.25 (t, J = 6.2 Hz, 3H), B m/z348 (M + H)⁺ amino-1H-pyrazol-5- 1.60-2.20 (m, 12H), 2.53-2.59 (m, 1H),2.70-2.75 (ES+), at 2.75 min, yl)piperidin-1-yl]-6- (m, 1H), 2.92-2.98(m, 2H), 3.21-3.47 (m, 4H), UV inactive azaspiro[3.4]octane-6- 4.01-4.20(m, 2H), 5.45 (s,1H), 3 × NH not carboxylate observed 1-20 Mixture ofdiastereomers: 3 and 38 b 400 MHz, CDCl₃) δ: 1.56-1.70 (m, 2H),1.79-2.01 B m/z 332 (M + H)⁺ methyl 2-[4-(1-methyl- (m, 8H), 2.05-2.25(m, 2H), 2.51-2.83 (m, 2H), (ES+), at 2.70 min,1H-pyrazol-5-yl)piperidin- 2.88-3.14 (m, 2H), 3.23-3.51 (m, 4H), 3.71(s, UV inactive 1-yl]-6- 3H), 3.83 (s, 3H), 6.03 (br, 1H), 7.34-7.43 (m,1H) azaspiro[3.4]octane-6- carboxylate 1-21 Isomer 2: ethyl 2-[4-(1- 2and 9 a (400 MHz, CDCl₃) δ: 1.18-1.30 (m, 3H), 1.67-2.30 B m/z 347 (M +H)⁺ methyl-1H-pyrazol-5- (m, 12H), 2.57-2.63 (m, 1H), 2.70-2.84 (m, 1H),(ES+), at 3.18 min, yl)piperidin-1-yl]-6 3.00-3.15 (m, 2H), 3.22-3.61(m, 4H), 3.81 (s, UV inactive azaspiro[3.4]octane-6- 3H), 4.11 (q, J =6.4 Hz, 2H), 6.04 (s, 1H), 7.37 (s, carboxylate 1H) 1-22 Isomer 2: ethyl2-[4-(1- 2 and 10 a (400 MHz, CDCl₃) δ: 1.14-1.32 (m, 3H), 1.54-1.71 Bm/z 347 (M + H)⁺ methyl-1H-pyrazol-3- (m, 2H), 1.78-2.12 (m, 10H),2.43-2.49 (m, 1H), (ES+), at 3.51 min, yl)piperidin-1-yl]-6- 2.60-2.78(m , 1H), 2.84-2.96 (m, 2H), 3.18-3.46 UV inactiveazaspiro[3.4]octane-6- (m, 4H), 3.84 (s, 3H), 4.03-4.20 (m, 2H), 7.13(s, carboxylate 1H), 7.32 (s, 1H) 1-23 Isomer 2: ethyl 2-[4-(1,3- 2 and41 b (400 MHz, DMSO-d₅) δ: 1.18 (t, J = 7.0 Hz, 3H), G m/z 334 (M + H)⁺oxazol-2-yl)piperidin-1- 1.57-1.73 (m, 2H), 1.73-1.91 (m, 6H), 1.92-2.05(ES+), at 5.37 min, yl]-6-azaspiro[3.4]octane- (m, 4H), 2.63-2.72 (m,2H), 2.73-2.85 (m, 2H), UV active 6-carboxylate 3.13-3.21 (m, 2H),3.25-3.34 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 8.01 (s, 1H), 7.12 (s, 1H).1-24 Isomer 2: methyl 2-[4- 3 and 42 b (400 MHz, DMSO-d₅) δ: 1.58-1.73(m, 2H), 1.73- G m/z 336 (M + H)⁺ (1,3-thiazol-2- 1.92 (m, 6H),1.96-2.10 (m, 4H), 2.65-2.74 (m, (ES+), at 5.15 min,yl)piperidin-1-yl]-6- 1H), 2.79-2.89 (m, 2H), 2.91-3.03 (m, 1H), 3.23-UV active azaspiro[3.4]octane-6- 3.32 (m, 4H), 3.58 (s, 3H), 7.61 (d, J= 3.4 Hz, carboxylate 1H), 7.72 (d, J = 3.4 Hz, 1H). 1-25 Isomer 2:ethyl 2-[4-(1,3- 2 and 42 b (400 MHz, DMSO-d₅) δ: 1.18 (t, J = 7.0 Hz,3H), F m/z 350 (M + H)⁺ thiazol-2-yl)piperidin-1- 1.59-1.74 (m, 2H),1.76-1.92 (m, 6H), 1.97-2.09 ES+), at 1.61 min,yl]-6-azaspiro[3.4]octane- (m, 4H), 2.63-2.75 (m, 1H), 2.80-2.90 (m,2H), UV active 6-carboxylate 2.92-3.05 (m, 1H), 3.14-3.20 (m, 2H),3.25-3.34 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 7.60 (d, J = 3.0 Hz, 1H),7.72 (d, J = 3.0 Hz, 1H) 1-26 Isomer 2: ethyl 2-[4-(4H- 1 and 17 f (400MHz, CDCl₃) δ: 1.15-1.38 (m, 3H), 1.77-3.21 E m/z 334 (M + H)⁺1,2,4-triazol-3- (m, 15H), 3.23-3.78 (m, 5H), 4.00-4.27 (m, 2H), (ES+),at 2.78 min, yl)piperidin-1-yl]-6- 8.42 (s, 1H), NH not observed UVinactive azaspiro[3.4]octane-6- carboxylate 1-27 Isomer 2: ethyl2-[4-(5- 2 and 23 as (400 MHz, CDCl₃) δ: 1.25 (t. J = 7.0 Hz, 3H), 1.34C m/z 362 (M + H)⁺ ethyl-1H-1,2,4-triazol-3- (t, J = 7.5 Hz, 3H),1.73-2.35 (m, 12H), 2.79 (q, (ES+), at 1.43 min, yl)piperidin-1-yl]-6- J= 7.5 Hz, 2H), 2.84-3.15 (m, 4H), 3.31-3.46 (m, UV activeazaspiro[3.4]octane-6- 4H), 4.11 (q, J = 7.0 Hz, 2H), NH not observedcarboxylate 1-28 Isomer 2: ethyl 2-[4- 2 and 43 b (400 MHz, DMSO-d₅) δ:1.18 (t, J = 7.0 Hz. 3H), G m/z 335 (M + H)⁺ (1,3,4-oxadiazol-2-1.62-1.74 (m, 2H), 1.75-1.94 (m, 6H), 1.95-2.06 (ES+), at 4.89 min,yl)piperidin-1-yl]-6- (m, 4H), 2.65-2.74 (m, 1H), 2.74-2.83 (m, 2H), UVactive azaspiro[3.4]octane-6- 2.93-3.01 (m, 1H), 3.14-3.21 (m, 2H),3.26-3.32 carboxylate (m, 2H), 4.00 (q, J = 7.0 Hz, 2H), 9.15 (s, 1H)1-29 Isomer 2: ethyl 2-[4-(3- 2 and 44 b (400 MHz, DMSO-d₅) δ: 1.18 (t,J = 7.0 Hz, 3H), F m/z 349 (M + H)⁺ methyl-1,2,4-oxadiazol-5- 1.62-1.74(m, 2H), 1.75-1.95 (m, 6H), 1.95-2.05 (ES+), at 1.63 min,yl)piperidin-1-yl]-6- (m, 4H), 2.33 (s, 3H), 2.65-2.72 (m, 1H), 2.72- UVactive azaspiro[3.4]octane-6- 2.81 (m, 2H), 2.93-3.03 (m, 1H), 3.14-3.20(m, carboxylate 2H), 3.25-3.33 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H) 1-30Isomer 2: ethyl 2-[4- 2, 28, 29 b (400 MHz, DMSO-d₅) δ: 1.17 (t, J =7.0, 3H), G m/z 351 (M + H)⁺ (1,2,4-thiadiazol-5- and 30 1.59-1.95 (m,8H), 1.95-2.20 (m, 4H), 2.39-2.93 (ES+), at 5.47 min,yl)piperidin-1-yl]-6- (m, 4H), 2.09-3.53 (m, 4H), 4.00 (q, J = 7.0 Hz,UV active azaspiro[3.4]octane-6- 2H), 8.82 (s, 1H) carboxylate 1-31Isomer 2: ethyl 2-[4-(1H- 2 and 31 b (400 MHz, DMSO-d₆) δ: 1.03-1.27 (m,3H), 1.88- F m/z 335 (M + H)⁺ tetrazol-5-yl)piperidin-1- 1.92 (m, 4H),1.92-2.26 (m, 6H), 2..39-2.63 (m, (ES+), at 1.56 min,yl]-6-azaspiro[3.4]octane- 2H), 2.66-2.87 (m, 3H), 3.00-3.40 (m, 4H),3.99 UV active 6-carboxylate (q, J = 7.0 Hz, 2H), 4.80-4.96 (m, 1H),8.93 (s, 1H) 1-32 Isomer 2: ethyl 2-[4-(1H- 2 and 11 a (400 MHz,DMSO-d₆) δ: 1.27 (t, J = 7.0 Hz, 3H), B m/z 332 (M + H)⁺pyrrol-1-yl)pipendin-1-yl]- 1.91-2.06 (m, 10H), 2.13-2.18 (m, 2H),2.81-2.67 (ES+), at 3.90 min, 6-azaspiro[3.4]octane-6- (m, 1H),3.00-3.04 (m, 2H), 3.30-3.43 (m, 4H), UV inactive carboxylate 3.95-4.00(m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 6.05 (s, 2H), 6.77 (t, J = 2.0 Hz,2H) 1-33 Isomer 2: ethyl 2-[4-(1H- 1 and 12 a (400 MHz, CDCl₃) δ: 1.18(t, J = 7.0 Hz, 3H), B m/z 333 (M + H)⁺ pyrazol-1-yl)piperidin-1-1.78-2.13 (m, 12H), 2.63-2.73 (m, 1H), 2.38-2.95 (ES+), at 3.14 min,yl]-6-azaspiro[3.4]octane- (m, 2H), 3.19-3.40 (m, 4H), 4.05 (q, J = 7.0Hz, UV inactive 6-carboxylate 2H), 4.09-4.13 (m, 1H), 6.20 (t, J = 2.0Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.44 (s, 1H) 1-34 Isomer 1: ethyl2-[4-(4- 1 and 13 d (400 MHz, CDCl₃) δ: 1.25 (t, J = 7.0 Hz, 3H), B m/z347 (M + H)⁺ methyl-1H-pyrazol-1- 1.79-2.01 (m, 9H), 2.06 (s, 3H),2.07-2.18 (m, (ES+), at 3.43 min, yl)piperidin-1-yl]-6- 3H), 2.65-2.78(m, 1H), 2.92-2.98 (m, 2H), 3.28- UV inactive azaspiro[3.4]octane-6-3.43 (m, 4H), 4.03-4.11 (m, 1H), 4.12 (q, J = 7.0 carboxylate Hz, 2H),7.18 (s, 1H), 7.28 (s, 1H) 1-34 Isomer 2: ethyl 2-[4-(4- 1 and 11 d (400MHz, CDCl₃) δ: 1.25 (t, J = 7.0 Hz, 3H), B m/z 347 (M + H)⁺methyl-1H-pyrazol-1- 1.81-2.19 (m, 9H), 2.07 (s, 3H), 2.10-2.16 (m,(ES+), at 3.55 min, yl)piperidin-1-yl]-6- 3H), 2.65-2.81 (m, 1H),2.93-2.99 (m, 2H), 3.21- UV inactive azaspiro[3.4]octane-6- 3.49 (m,4H), 4.10-4.12 (m, 1H), 4.12 (q, J = 7.0 carboxylate Hz, 2H), 7.20 (s,1H), 7.28 (s, 1H) 1-35 Isomer 2: ethyl 2-[4-(1H- 1 and 18 f (400 MHz,CDCl₃) δ: 1.19 (t, 3H), 1.76-2.10 (m, E m/z 334 (M + H)⁺1,2,3-triazol-1- 10H), 2.10-2.24 (m, 2H), 2.62-2.79 (m, 1H), 2.84-(ES+), at 2.90 min, yl)piperidin-1-yl]-6- 3.02 (m, 2H), 3.17-3.28 (m,2H), 3.28-3.42 (m, UV inactive azaspiro[3.4]octane-6- 2H), 3.98-4.12 (q,J = 7.0 Hz, 2H), 4.38-4.59 (m, carboxylate 1H), 7.54 (s, 1H) 7.64 (s,1H). 1-36 Isomer 2: ethyl 2-[4-(1H- 1, 16 f (400 MHz, CDCl₃) δ:1.21-1.81 (m, 3H), 1.84-2.12 E m/z 334 (M + H)⁺ 1,2,4-triazol-1- and 56(m, 10H), 2.13-2.20 (m, 2H), 2.62-2.88 (m, 1H), (ES+), at 2.88 min,yl)piperidin-1-yl]-6- 2.88-3.08 (m, 2H), 3.22-3.33 (m, 2H), 3.34-3.47 UVinactive azaspiro[3.4]octane-6- (m, 2H), 4.06-4.15 (m, 2H), 4.16-4.25(m, 1H), carboxylate 7.93 (s, 1H), 8.10 (s, 1H). 1-37 Isomer 2: ethyl2-[4- 2 and 47 b (400 MHz, DMSO-d₅) δ: 1.17 (t, J = 7.0 Hz, 3 H), H m/z349 (M + H)+ hydroxy-4-(1H-imidazol- 1.65-1.88 (m, 6 H), 1.93-2.04 (m, 4H), 2.14-2.26 (ES+) at 7.05 min, 2-yl)piperidin-1-yl]-6- (m, 2H),2.36-2.47 (m, 2 H), 2.62-2.72 (m, 1 H), UV active azaspiro[3.4]octane-6-3.12-3.20 (m, 2 H), 3.23-3.31 (m, 2H), 4.00 (q, J = carboxylate 7.0 Hz,2H), 5.04 (s, 1 H), 6.77 (s, 1 H), 6.94 (s, 1 H), 11.71 (s, 1 H) 1-38Isomer 2: ethyl 2-[4-(1H- 2 and 48 b (400 MHz, DMSO-d₅) δ: 1.16 (t, J =7.0 Hz, 3 H), F m/z 363 (M + H)+ imidazol-2-yl)-4- 1.71-1.86 (m, 6 H),1.89-2.08 (m, 6 H), 2.53-2.58 (ES+) at 1.41 min,methoxypiperidin-1-yl]-6- (m, 2 H), 2.59-2.71 (m, 1 H), 2.84 (s, 3 H),3.11- UV active azaspiro[3.4]octane-6- 3.20 (m, 2 H), 3.22-3.29 (m, 2H),4.00 (q, J = 7.0 carboxylate Hz, 2H), 6.82 (s, 1 H), 7.09 (s, 1 H),11.94 (s, 1 H) 1-39 Isomer 2: ethyl 2-[4- 2 and 49 b (400 MHz, DMSO-d₅)δ: 1.17 (t, J = 7.0 Hz, 3 H), G m/z 363 (M + H)+ hydroxy-4-(1-methyl-1H-1.70-1.90 (m, 6 H), 1.93-2.04 (m, 4 H), 2.11-2.24 (ES+) at 4.05 min,imidazol-2-yl)piperidin-1- (m, 2H), 2.42-2.47 (m, 2 H), 2.63-2.72 (m, 1H), UV active yl]-6-azaspiro[3.4]actane- 3.11 -3.18 (m, 2 H), 3.24-3.30(m, 2H), 3.77 (s, 6-carboxylate 3H), 4.00 (q, J = 7.0 Hz, 2H), 5.09 (s,1 H), 6.70 (s, 1 H), 7.00 (s, 1 H) 1-40 Isomer 2: ethyl 2-[4- 2 and 60 b(400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3H) F m/z 377 (M + H)+methoxy-4-(1-methyl-1H- 1.72-2.21 (m, 12 H), 2.60-2.72 (m, 1 H), 2.87(s, 3 (ES+) at 1.50 min, imidazol-2-yl)piperidin-1- H), 3.11-3.18 (m, 2H), 3.24-3.30 (m, 4H), 3.77 (s, UV active yl]-6-azaspiro[3.4]octane-3H), 4.00 (q, J = 7.0 Hz, 2H), 6.78 (s, 1 H), 7.11 6-carboxylate (s, 1H) 1-41 Isomer 2: ethyl 2-[4- 2 and 24 as (400 MHz, CDCl₃) δ: 1.24 (t, J= 7.0 Hz, 3H), C m/z 363 (M + H)⁺ methyl-4-(3-methyl-1 1.35-1.40 (m,3H), 1.56-2.12 (m, 11H), 2.30-2.39 (ES+), at 1.70 min,oxadiazol-5-yl)piperdin-1- (m, 2H), 2.40 (s, 3H), 2.57-2.78 (m, 2H),3.21- UV active yl]-6-azaspiro[3.4]octane- 3.45 (m, 4H), 4.11 (q, J =7.0 Hz, 2H) 6-carboxylate 1-42 Isomer 2: methyl 2-[4-(4- 3 and 73 at(400 MHz, CD₃OD) δ: 1.82-2.19 (m, 15 H), 2.82 E m/z 333 (M + H)⁺methyl-1H- pyrazol-1- (quin, J = 7.9 Hz, 1 H), 2.92-3.05 (m, 2 H), 3.27(s, (ES+), at 2.77 min, yl)piperidin-1-yl]-6- 2 H), 3.34-3.44 (m, 2 H),3.66 (s, 3 H), 4.02-4.16 UV active azaspiro[3.4]octane-6- (m, 1 H), 7.27(s, 1 H), 7.44 (s, 1 H) carboxylate 1-43 Isomer 2: ethyl 2-[4-(1,2- 2and 74 at (400 MHz, methanol-d₄) δ: 1.24 (t, J = 7.0 Hz, 3 E m/z 334(M + H)⁺ oxazol-3-yl)piperidin-1- H), 1.65-1.82 (m, 2H), 1.84-2.20 (m,10 H), 2.72- (ES+), at 3.14 min, yl]-6-azaspiro[3.4]octane- 3.02 (m,4H), 3.27 (s, 2 H), 3.39 (q, J = 6.6 Hz, 2 UV active 6-carboxylate H),4.09 (q, J = 7.0 Hz, 2 H), 6.18 (s, 1 H), 8.27 (s, 1 H) 1-44 Isomer 2:ethyl 2-[4-(3- 2 and at (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.2 Hz, 3 H), Em/z 347 (M + H)⁺ methyl-1H-pyrazol-1- 119 1.82-2.17 (m, 12 H), 2.22 (s,3 H), 2.83 (quin, J = (ES+), at 3.11 min, yl)pipendin-1-yl]-6- 7.9 Hz, 1H), 3.00 (d, J = 9.4 Hz, 2 H), 3.27 (s, 2 UV activeazaspiro[3.4]octane-6- H), 3.39 (q, J = 6.5 Hz, 2 H), 4.01-4.15 (m, 3H), carboxylate 5.04 (d, J = 2.3 Hz, 1 H), 7.52 (d, J = 2.3 Hz, 1 H)1-45 Isomer 2: methyl 2-[4-(3- 3 and at (400 MHz, CD₃OD) δ: 1.81-2.17(m, 12 H), 2.22 E m/z 333 (M + H)⁺ methyl-1H-pyrazol-1- 119 (s, 3 H),2.83 (quin, J = 7.9 Hz, 1 H), 2.95-3.05 (m, (ES+), at 2.84 min,yl)piperidin-1-yl]-6- 2 H), 3.27 (s, 2 H), 3.39 (t, J = 6.4 Hz, 2 H),3.66 UV active azaspiro[3.4]octane-6- (s, 3 H), 4.00-4.13 (m, 1 H), 6.04(d, J = 2.3 Hz, 1 carboxylate H), 7.52 (d, J = 2.3 Hz, 1 H) 1-46 Isomer2: methyl 2-[4-(1- 3 and at (400 MHz, CD₃OD) δ: 1.37 (t, J = 7.2 Hz, 3H), E m/z 347 (M + H)⁺ ethyl-1H-pyrazol-5- 120 1.60-1.78 (m, 2 H),1.84-2.01 (m, 8 H), 2.07-2.18 (ES+), at 2.89 min, yl)piperidin-1-yr]-6-(m, 2 H), 2.67-2.88 (m, 2 H), 2.99 (d, J = 11.7 Hz, UV activeazaspiro[3.4]octane-6- 2 H), 3.27 (s, 2 H), 3.39 (t, J = 6.4 Hz, 2 H),3.66 carboxylate (s, 3 H), 4.12 (q, J = 7.3 Hz, 2 H), 6.09 (d, J = 2.0Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H) 1-47 Isomer 2: ethyl 2-[4-(1- 2 andat (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.2 Hz, 3 H), E m/z 361 (M + H)⁺ethyl-1H-pyrazol-5- 120 1.37 (t, J = 7.22 Hz, 3 H), 1.60-1.78 (m, 2 H),(ES+), at 3.23 min, yl)piperidin-1-yl]-6- 1.82-2.04 (m, 8 H), 2.07-2.19(m, 2 H), 2.67-2.87 UV active azaspiro[3.4]octane-6- (m, 2 H), 2.99 (d.J = 11.7 Hz, 2 H), 3.27 (s, 2 H), carboxylate 3.39 (q, J = 6.6 Hz, 2 H),4.05-4.18 (m, 4 H), 6.09 (d, J = 1.6 Hz, 1 H), 7.38 (d, J = 1.6 Hz, 1 H)1-48 Isomer 2: methyl 2-[4-(1- 3 and as (400 MHz, CDCl₃) δ: 0.93 (t, J =7.4 Hz, 3 H), B m/z 361 (M + H)⁺ propyl-1H-pyrazol-5- 173 1.58-2.19 (m,13 H), 2.52-2.87 (m, 2 H), 2.93-3.12 (ES+), at 3.66 min,yl)piperidin-l-yl]-5- (m, 2 H), 3.23-3.51 (m, 5 H), 3.68 (s, 3 H), 4.00(t, UV active azaspiro[3.4]octane-6- J = 7.3 Hz, 2 H), 6.05 (br. s., 1H), 7.42 (s, 1 H) carboxylate 1-49 Isomer 2: ethyl 2-[4-(1- 2 and as(400 MHz, CDCl₃) δ: 0.93 (t, J = 7.4 Hz, 3 H), B m/z 375 (M + H)⁺propyl-1H-pyrazol-5- 173 1.25 (t, J = 7.0 Hz, 3 H), 1.56-2.20 (m, 13 H),(ES+), at 4.16 min, yl)piperidin-1-yl]-6- 2.51-2.83 (m, 2 H), 2.90-3.12(m, 2 H), 3.25-3.50 UV active azaspiro[3.4]octane-6- (m, 5 H), 4.00 (t,J = 7.4 Hz, 2 H) 4.12 (q, J = 7.3 carboxylate Hz, 2 H), 6.05 (br. s., 1H), 7.42 (s, 1 H) 1-50 Isomer 2: ethyl 2-[4-(1,3- 2 and as (400 MHz,CDCl₃) δ: 1.25 (t, J = 7.0 Hz, 3 H), B m/z 350 (M + H)⁺thiazol-4-yl)piperidin-1- 164 1.51-2.31 (m, 11 H), 2.63-3.16 (m, 4 H),3.20-3.47 (ES+), at 1.39 min, yl]-6-azaspiro[3.4]octane- (m, 5 H), 4.12(q, J = 7.3 Hz, 2 H), 5.90-7.05 (br. weakly UV active 6-carboxylate s.,1 H), 8.76 (s, 1 H) 1-51 Isomer 2: ethyl 2-{4-[1-(2- Example g (400 MHz,CDCl₃) δ: 1.25 (1, J = 7.2 Hz, 3 H), B m/z 391 (M + H)⁺methoxyethyl)-1H- 1-1 and 1.74-2.15 (m, 12 H), 2.72 (br. s., 2 H), 3.01(br. s., (ES+), at 3.56 min, imidazol-2-yl]piperidin-1- 165 2 H),3.28-3.46 (m, 4 H), 3.32 (s, 3 H), 3.61 (t, J = weakly UV activeyl}-6-azaspiro[3.4]octane- 5.5 Hz, 2 H), 4.04 (t, J = 5.5 Hz, 2 H), 4.11(q, J = 6-carboxylate 7.2 Hz, 2 H), 6.89 (s, 1 H), 6.96 (s, 1 H) 1-52Isomer 2: ethyl 2-{4-[1- Example h (400 MHz, CDCl₃) δ: 1.25 (t, J = 7.0Hz, 3 H), B m/z 372 (M + H)⁺ (cyanomethyl)-1H- 1-1 and 1.47-2.32 (m, 11H), 2.64-3.26 (m, 4 H), 3.27-3.50 (ES+), at 3.24 min,imidazol-2-yl]piperidin-1- 166 (m, 5 H), 4.06-4.17 (m, 2 H), 4.90 (s, 2H), 6.97 weakly UV active yl}-6-azasoiro[3.4]octane- (br. s., 1 H), 7.02(s, 1 H) 6-carboxylate 1-53 Isomer 2: (2-{1-[6- Example i (400 MHz,DMSO-d₆) δ: 1.18 (t, J = 7.2 Hz, 3 H), B m/z 391 (M + H)⁺(ethoxycarbonyl)-6- 1-1 and 1.59-1.94 (m, 10 H), 1.95-2.08 (m, 2 H),2.80-2.93 (ES+), at 1.57 min, azaspiro[3.4]oct-2- 167 (m, 2 H),3.95-4.07 (q, J = 7.0 Hz, 2 H), 4.29-4.38 UV inactiveyl]piperidin-4-yl}-1H- (br. s., 2 H), 6.70 (s, 1 H), 6.89 (s, 1 H). 7protons imidazol-1-yl)acetic acid obscured by water peak. 1-54 Isomer 2:ethyl 2-(4-{1-[2- Example i (400 MHz, CDCl₃) δ: 1.25 (t, J = 7.2 Hz, 3H), B m/z 404 (M + H)⁺ methylamino)-2- 1-53 and 1.71-2.33 (m, 11 H),2.68-3.20 (m, 4 H), 2.81 (d, (ES+), at 2.18 min,oxoethyl]-1H-imidazol-2- 168 J = 4.7 Hz, 3 H), 3.27-3.48 (m, 5 H), 4.11(q, J = weakly UV active yl}piperidin-1-yl)-6- 7.0 Hz, 2 H), 4.66 (s,2H), 6.01 (br. s, 1 H), 6.91 azaspiro[3.4]octane-6- (d, J = 5.5 Hz, 1H), 7.05 (s, 1 H) carboxylate 1-55 Isomer 2: methyl 2-[4- 3 and as (300MHz, CDCl3) δ: 1.51-2.26 (m, 15 H), 2.56- B m/z 347 (M + H)⁺(1,4-dimethyl-1H-pyrazol- 177 2.82 (m, 2 H), 2.92-3.14 (m, 2 H),3.20-3.53 (m, 4 (ES+), at 4.22 min, 3-yl)piperidin-1-yl]-6- H), 3.69 (s,3 H), 3.83 (s, 3 H), 7.18 (s, 1 H) UV active azaspiro[3.4]octane-6-carboxylate 1-56 Isomer 2: ethyl 2-[4-(1,4- 2 and as (400 MHz, CDCl₃) δ:1.27 (t, J = 7.0 Hz, 3 H), B m/z 361 (M + H)⁺ dimethyl-1H-pyrazol-3- 1771.63 (s, 5 H), 1.68-2.25 (m, 10 H), 2.43-2.75 (m, 2 (ES+), at 3.70 min,yl)piperidin-1-yl]-6- H), 2.84-3.06 (m, 2 H), 3.29-3.43 (m, 4 H), 3.82UV active azaspiro[3.4]octane-6- (br. s., 3 H), 4.10-4.18 (m, 2 H), 7.18(s, 1 H) carboxylate 1-57 Isomer 2: methyl 2-[4- 3 and as (300 MHz,CDCl₃) δ: 1.53-2.20 (m, 15 H), 2.54- B m/z 347 (M + H)⁺(1,4-dimethyl-1H-pyrazol- 178 2.90 (m, 2 H), 2.94-3.17 (m, 2 H),3.27-3.50 (m, 4 (ES+), at 4.74 min, 5-yl)piperidin-1-yl]-6- H), 3.88 (s,3 H), 3.77 (s, 3 H), 7.04 (s, 1 H) UV active azaspiro[3.4]octane-6-carboxylate 1-58 Isomer 2: ethyl 2-[4-(1,4- 2 and as (400 MHz, CDCl₃) δ:1.25 (t, J = 7.0 Hz, 3 H), dimethyl-1H-pyrazol-5- 178 1.67-2.19 (m, 15H), 2.54-2.82 (m, 2 H), 2.93-3.12 B m/z 361 (M + H)⁺yl)piperidin-1-yl]-6- (m, 2 H), 3.25-3.48 (m, 4 H), 3.77 (s, 3 H), 4.11(ES+), at 4.07 min, azaspiro[3.4]octane-6- (q, J = 7.3 Hz, 2 H), 7.04(s, 1 H) UV active carboxylate 1-59 Isomer 2: ethyl 2-[4-(1- 2 and b(400 MHz, CD₃OD) δ: 1.25 (t, J = 7.2 Hz, 3 H), I m/z 375 (M + H)⁺ethyl-4-methyl-1H- 173 1.33 (t, J = 7.2 Hz, 3 H), 1.77 (d, J = 10.7 Hz,2 (ES+), at 4.22 min, pyrazol-5-yl)piperidin-1- H), 1.90-2.10 (m, 8 H),2.10-2.24 (m, 2 H), 2.13 weakly UV active yl]-6-azaspiro[3.4]octane- (s,3 H), 2.79-2.96 (m, 2 H), 3.08 (d, J = 8.9 Hz, 2 6-carboxylate H),3.28-3.30 (m, 2 H), 3.37-3.45 (m, 2 H), 4.07- 4.18 (m, 4 H), 7.18 (s, 1H) 1-60 Isomer 2: ethyl 2-[4-(4- 2 and b (400 MHz, CD₃OD) δ: 1.18-1.40(m, 6 H), 1.96- I m/z 375 (M + H)⁺ ethyl-1-methyl-1H- 251 2.10 (m, 3H),2.11-2.31 (m, 5H), 2.35-2.43 (m, (ES+), at 4.36 min,pyrazol-5-yl)piperidin-1- 2H), 2.59 (q, J = 7.5 Hz, 2H), 2.67-2.84 (m,2H), UV active yl]-6-azaspiro[3.4]octane- 3.07-3.23 (m, 1H), 3.37-3.61(m, 6H), 3.85 (s, 6-carboxylate 3H), 4.13 (q, J = 6.8 Hz, 3H), 7.28 (s,1H). 1-61 Isomer 2: ethyl 2-[4-(2H- 2 and ak (400 MHz, CD₃OD) δ: 1.27(t, J = 7.1 Hz, 3H), I m/z 334 (M + H)⁺ 1,2,3-triazol-2- 247 1.88-2.02(m, 4H), 2.12-2.28 (m, 8H), 2.81-2.92 (ES+), at 3.90 min,yl)piperidin-1-yl]-6- (m, 1H), 2.93-3.05 (m, 2H), 3.27-3.36 (m, 2H), UVactive azaspiro[3.4]octane-6- 3.37-3.46 (m, 2H), 4.12 (q, J = 7.1 Hz,2H), 4.51- carboxylate 4.61 (m, 1H), 7.69 (s, 2H). 1-62 Isomer 2: ethyl2-[4-(1H- 2 and b (400 MHz, CD₃OD) δ: 1.25 (t, J = 7.0 Hz, 3 H), I m/z335 (M + H)⁺ tetrazol-1-yl)piperidin-1- 215 1.90-2.00 (m, 4 H),2.05-2.21 (m, 6 H), 2.21-2.32 (ES+), at 3.47 min,yl]-6-azaspiro[3.4]octane- (m, 2 H), 2.81-2.91 (m, 1 H), 3.02 (d, J =7.3 Hz, 2 weakly UV active 6-carboxylate H), 3.28 (s, 2 H), 3.36-3.44(m, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.60-4.71 (m, 1 H), 9.26 (s, 1 H)1-63 Isomer 2: ethyl 2-[4-(5- 2 and b (400 MHz, CD₃OD) δ: 1.20-1.34 (m,4H), 1.90- I m/z 345 (M + H)⁺ methyl-1H-tetrazol-1- 255 2.03 (m,4H),2.04-2.32 (m, 9H), 2.61 (s, 3H), (ES+), at 3.44 min,yl)piperidin-1-yl]-6- 2.84-2.93 (m, 1H), 3.02-3.13 (m, 2H), 3.30-3.52 UVactive azaspiro[3.4]octane-6- (m, 2H), 4.12 (q, J = 7.1 Hz, 2H),4.42-4.54 (m, carboxylate 1H). 1-64 Isomer 2: ethyl 2-[4-(1- 2 and b(400 MHz, CDCl₃) δ: 1.25 , J = 7.2 Hz, 3 H), 1.82- I m/z 349 (M + H)⁺methyl-1H-tetrazol-5- 195 2.31 (m, 8 H), 2.74-3.72 (m, 12 H), 4.02-4.16(m, (ES+), at 3.40 min, yl)piperidin-1-yl]-6- 5 H) UV activeazaspiro[3.4]octane-6- carboxylate 1-65 Isomer 2: ethyl 2-[4-(1- 2 andak (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 H), I m/z 363 (M + H)⁺ethyl-1H-tetrazol-5- 320 1.42 (t, J = 7.3 Hz, 3 H), 1.62-1.96 (m, 10 H),(ES⁺), at 3.75 min, yl)piperidin-1-yl]-6- 1.96-2.07 (m, 2 H), 2.66-2.76(m, 1 H), 2.82-2.91 UV active azaspiro[3.4]octane-6- (m, 2 H), 2.95-3.06(m, 1 H), 3.17 (d, J = 7.0 Hz, 2 carboxylate H), 3.25-3.32 (m, 2 H),4.00 (q, J = 7.2 Hz, 2 H), 4.39 (q, J = 7.3 Hz, 2 H) 1-66 Isomer 2:ethyl 2-[4-(2- 2 and ak (400 MHz, DMSO-d₅) δ: 1.17 (t, J = 7.2 Hz, 3 H),I m/z 363 (M + H)⁺ ethyl-2H-tetrazol-5- 319 1.49 (t, J = 7.3 Hz, 3 H),1.61-1.75 (m, 2 H), 1.75- (ES⁺), at 4.06 min, yl)piperidin-1-yl]-6- 1.92(m, 6 H), 1.92-2.06 (m, 4 H), 2.63-2.74 (m, 1 UV activeazaspiro[3.4]octane-6- H), 2.79 (d, J = 11.3 Hz, 2 H), 2.88 (tt, J =11.4, carboxylate 4.0 Hz, 1 H), 3.16 (d, J = 6.7 Hz, 2 H), 3.28 (q, J =7.0 Hz, 2 H), 4.00 (q, J = 7.0 Hz, 2 H), 4.64 (q, J = 7.3 Hz, 2 H) 1-67Isomer 2: ethyl 2-[4-(1- 2 and b (400 MHz, DMSO-d₆) δ: 1.12-1.26 (m, 7H), 1.66- I m/z 375 (M + H)⁺ cyclopropyl-1H-tetrazol-5- 218 1.94 (m, 8H), 1.94-2.08 (m, 4 H), 2.66-2.79 (m, 1 (ES+), at 3.88 min,yl)piperidin-1-yl]-6- H), 2.89 (d, J = 11.6 Hz, 2 H), 3.03-3.14 (m, 1H), weakly UV active azaspiro[3.4]octane-6- 3.18 (d, J = 7.0 Hz, 2 H),3.26-3.35 (m, 2 H), 3.84 carboxylate (s, 1 H), 3.96-4.07 (m, 2 H) 1-68Isomer 2: (1,1-²H₂)ethyl 2- 302 and j (400 MHz, DMSO-d₆) δ: 1.13 (s, 3H), 1.73-2.03 E m/z 335 (M + H)⁺ [4-(1H-pyrazol-1- 304 (m, 12 H),2.61-2.74 (m, 1 H), 2.78-2.88 (m, 2 H), (ES⁺), at 3.59 min,yl)piperidin-1-yl]-6- 3.14 (d, J = 6.2 Hz, 2 H), 3.26 (q, J = 6.6 Hz, 2H), UV inactive azaspiro[3.4]octane-6- 4.08-4.17 (m, 1 H), 6.20 (t, J =2.0 Hz, 1 H), 7.37- carboxylate 7.44 (m, 1 H), 7.71-7.81 (m, 1 H) 1-69Isomer 2: (2,2,2-²H₃)ethyl 302 and j (400 MHz, DMSO-d₆) δ: 1.73-2.03 (m,12 H), E m/z 336 (M + H)⁺ 2-[4-(1H-pyrazol-1- 305 2.61-2.74 (m, 1 H),2.84 (d, J = 7.8 Hz, 2 H), 3.14 (ES⁺), at 3.58 min,yl)piperidin-1-yl]-6- (d, J = 6.2 Hz, 2 H), 3.26 (q, J = 6.6 Hz, 2 H),3.96 UV inactive azaspiro[3.4]octane-6- (s, 2 H), 4.07-4.17 (m, 1 H),6.20 (t, J = 2.0 Hz, 1 carboxylate H), 7.35-7.45 (m, 1 H), 7.68-7.80 (m,1 H) 1-70 Isomer 2: (²H₅)ethyl 2-[4- 302 and j (400 MHz, DMSO-d₅) δ:1.73-2.03 (m, 12 H), E m/z 338 (M + H)⁺ (1H-pyrazol-1- 303 2.68 (t, J =7.4 Hz, 1 H), 2.84 (d, J = 7.8 Hz, 2 H), (ES⁺), at 3.58 min,yl)piperidin-1-yl]-6- 3.14 (d, J = 6.2 Hz , 2 H), 3.22-3.29 (m, 2 H), UVinactive azasoiro[3.4]octane-6- 4.07-4.15 (m, 1 H), 6.20 (t, J = 2.0 Hz,1 H), 7.36- carboxylate 7.43 (m, 1 H), 7.75 (m, 1 H) 1-71 Isomer 2:(1,1-²H₂)ethyl 2- 306 and j (400 MHz, DMSO-d₅) δ: 1.13 (s, 3 H), 1.47(q, J = E m/z 349 (M + H)⁺ [4-(1-methyl-1H-pyrazol- 304 11.8 Hz, 2 H),1.65-1.94 (m, 8 H), 1.94-2.03 (m, 2 (ES⁺), at 3.59 min,5-yl)piperidin-1-yl]-6- H), 2.56-2.72 (m, 2 H), 2.82 (d, J = 11.3 Hz, 2H), UV inactive azaspiro[3.4]octane-6- 3.13 (d, J = 6.2 Hz, 2 H),3.23-3.28 (m, 2 H), 3.68- carboxylate 3.74 (s, 3 H), 6.02 (s, 1 H), 7.25(d, J = 1.6 Hz, 1 H) 1-72 Isomer 2: (2,2,2-²H₃)ethyl 306 and j (400 MHz,DMSO-d₅) δ: 1.47 (q, J = 12.0 Hz, 2 E m/z 350 (M + H)⁺2-[4-(1-methyl-1H- 305 H), 1.72-1.93 (m, 8 H), 1.93-2.03 (m, 2 H), 2.56-(ES⁺), at 3.58 min, pyrazol-5-yl)piperidin-1- 2.71 (m, 2 H), 2.82 (d, J= 10.2 Hz, 2 H), 3.13 (d, UV inactive yl]-6-azaspiro[3.4]octane- J = 5.9Hz, 2 H), 3.22-3.29 (m, 2 H), 3.68-3.75, (s, 6-carboxylate 3 H), 3.96(s, 2 H), 6.02 (s, 1 H), 7.25 (d, J = 1.6 Hz, 1 H) 1-73 Isomer 2:(²H₅)ethyl 2-[4- 306 and j (400 MHz, DMSO-d₅) δ: 1.40-1.54 (m, 2 H),1.67- E m/z 352 (M + H)⁺ (1-methyl-1H-pyrazol-5- 303 1.93 (m, 8 H),1.94-2.05 (m, 2 H), 2.57-2.71 (m, 2 (ES⁺), at 3.56 min,yl)piperidin-1-yl]-6- H), 2.82 (d, J = 10.9 Hz, 2 H), 3.13 (d, J = 5.9Hz, UV inactive azaspiro[3.4]octane-6- 2 H), 3.22-3.28 (m, 2 H), 3.72(s, 3 H), 6.02 (s, 1 carboxylate H), 7.23-7.28 (m, 1 H) 2-1 Isomer 2:ethyl 2-[4- 2 and 53 m (400 MHz, DMSO-d₅) δ: 1.16 (t, J = 7.1 Hz, 3 H),F m/z 336 (M + H)⁺ (pyrrolidin-2-yl)piperidin- 1.49-1.87 (m, 13 H), 1.97(t, J = 9.2 Hz, 2 H), (ES+), at 1.70 min, 1-yl]-6- 2.55-2.35 (m, 9 H),3.14 (d, J = 6.1 Hz, 2 H), 3.24- UV inactive azaspiro[3.4]octane-6- 3.27(m, 1 H), 4.00 (q, J = 7.1 Hz, 2 H), NH not carboxylate observed 2-2Isomer 2: ethyl 2-[4-(1- 122 and k (400 MHz, CDCl₃) δ: 1.17-1.57 (m, 5H), 1.59- G m/z 364 (M + H)⁺ formylpyrrolidin-2- 63 2.30 (m, 14 H),2.57-2.73 (m, 1 H), 2.84-3.01 (m, (ES+), at 5.07 min,yl)piperidin-1-yl]-6- 2 H), 3.17-3.51 (m, 6 H), 3.55-3.75 (m, 2 H), 4.12UV active azaspiro[3.4]octane-6- (q, J = 7.0 Hz, 2 H), 8.19-8.31 (m, 1H) carboxylate 2-3 Isomer 2: ethyl 2-[4-(1- 122 and m (400 MHz, CDCl₃)δ: 1.22-1.31 (m, 3 H), 1.53- G m/z 378 (M + H)⁺ acetylpyrrolidin-2- 601.77 (m, 11 H), 1.78-1.99 (m, 6 H), 2.00- 2.12 (m, (ES+), at 5.22 min,yl)piperidin-1-yl]-6- 5 H), 2.58-2.69 (m, 1 H), 2.84-2.99 (m, 2 H),3.22- UV active azaspiro[3.4]octane-6- 3.33 (m, 2 H), 3.34-3.53 (m, 3H), 4.13 (q, J = 7.2 carboxylate Hz, 2 H) 2-4 Isomer 2: ethyl 2-{4-[1-122 and L (400 MHz, CD₃OD) δ: 1.27 (t, J = 7.1 Hz, 3 H), G m/z 432 (M +H)⁺ (trifluoroacetyl)pyrrolidin- 62 1.30-1.68 (m, 6 H), 1.74-2.21 (m, 12H), 2.75-2.90 (ES+), at 6.50 min, 2-yl]piperidin-l-yl}-6- (m, 1 H), 3.00(d, J = 10.4 Hz, 2 H), 3.39-3.45 (m, UV active azaspiro[3.4]octane-6- 2H), 3.51-3.61 (m, 1 H), 3.75-3.87 (m, 1 H), 4.11 carboxylate (q, J = 7.1Hz, 2 H), 4.15-4.23 (m, 1 H), 4.64 (br. s., 1 H) 2-5 Isomer 2: methyl2-[4-(1- 323 and m (400 MHz, DMSO-d₅) δ: 0.97 (t, J = 7.1 Hz, 3 H), Gm/z 378 (M + H)⁺ propanoylpyrrolidin-2- 54 1.11-1.27 (m, 2 H), 1.36-1.62(m, 4 H), 1.66-1.89 (ES+), at 5.21 min, yl)piperidin-1-yl]-6- (m, 9 H),1.93-2.02 (m, 2 H), 2.24 (q, J = 7.1 Hz, 2 UV activeazaspiro[3.4]octane-6- H), 2.56-2.65 (m, 1 H), 2.74-2.86 (m, 2 H), 3.14carboxylate (d, J = 2.8 Hz, 2 H), 3.22-3.30 (m, 3 H), 3.39-3.47 (m, 1H), 3.56 (s, 3 H), 3.84-3.92 (m, 1H) 2-6 Isomer 2: ethyl 2-[4-(1- 122and m (400 MHz, DMSO-d₅) δ: 0.93-0.99 (m, 3 H), 1.16 G m/z 392 (M + H)⁺propanoylpyrrolidin-2- 54 (t, J = 7.0 Hz, 3 H), 1.20-1.27 (m, 1 H),1.35-1.44 (ES+), at 5.27 min, yl)piperirlin-1-yl]-6- (m, 2 H), 1.45-1.62(m, 2 H), 1.64-1.89 (m, 7 H), UV active azaspiro[3.4]octane-6- 1.90-2.01(m, 2 H), 2.19-2.29 (m, 2 H), 2.54-2.63 carboxylate (m, 3 H), 2.78 (d, J= 11.3 Hz, 2 H), 3.14 (d. J = 6.1 Hz, 2 H), 3.22-3.30 (m, 2 H),3.39-3.48 (m, 3 H), 3.76-3.91 (m, 1 H), 3.99 (q, J = 7.0 Hz, 2 H) 2-7Isomer 2: ethyl 2-{4-[(2S)- 54 and m (400 MHz, DMSO-d₆) δ: 0.92-1.00 (m,3 H), 1.12- F m/z 392 (M + H)⁺ 1-propanoylpyrrolidin-2- 127 1.28 (m, 6H), 1.32-1.63 (m, 4 H), 1.64-1.90 (m, (ES+), at 1.69 min,yl]piperidin-1-yl)-6- 10 H), 1.92-2.03 (m, 2 H), 2.19-2.29 (m, 2 H), UVactive azaspiro[3.4]octane-6- 2.73-2.88 (m, 2 H), 3.14 (d, J = 5.5 Hz, 2H), 3.23- carboxylate 3.30 (m, 2 H), 3.38-3.47 (m, 1 H), 3.74-3.93 (m, 1H), 4.00 (q, J = 7.0 Hz, 2 H) 2-8 Isomer 2: ethyl 2-{4-[(2S)- 59 and m(400 MHz, CD₃OD) δ: 0.73-0.87 (m, 3 H), 0.88- E m/z 404 (M + H)⁺1-(cyclopropylcarbonyl) 127 1.03 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H),1.30-1.46 (ES+), at 3.49 min, pyrrolidin-2-yl]piperidin- (m, 2 H),1.49-2.03 (m, 15 H), 2.04-2.15 (m, 2 H), UV inactive 1-yl}-6- 2.67-2.82(m, 1 H), 2.89-3.01 (m, 2 H), 3.25 (s, 2 azaspiro[3.4]octane-6- H),3.34-3.42 (m, 2 H), 3.63 (s, 1 H), 4.01-4.15 carboxylate (m, 3 H) 2-9Isomer 2: ethyl 2-{4-[(2S)- 60 and m (400 MHz, CD₃OD) δ: 1.24 (t, J =7.1 Hz, 3 H), E m/z 418 (M + H)⁺ 1-(cyclobutylcarbonyl) 127 1.28-1.61(m, 5 H), 1.66-2.28 (m, 20 H), 2.67-2.78 (ES+), at 3.67 min,pyrrolidin-2-yl]piperidin- (m, 1 H), 2.88-2.99 (m, 2 H), 3.25 (s, 2 H),3.35- UV inactive 1-yl}-6- 3.52 (m, 3 H), 3.99-4.05 (m, 1 H), 4.09 (q, J= 7.1 azaspiro[3.4]octane-6- Hz, 2 H) carboxylate 2-10 Isomer 2: methyl2-{4-[1- 55 and m (400 MHz, DMSO-d₈) δ: 1.07-1.26 (m, 2 H), 1.38- G m/z380 (M + H)⁺ (methoxycarbonyl) 323 1.49 (m, 2 H), 1.50-1.62 (m, 2 H),1.69-1.78 (m, 6 (ES+), at 5.62 min, pyrrolidin-2-yl]piperidin- H),1.78-1.88 (m, 2 H), 1.93-2.01 (m, 2 H), 2.54- UV active 1-yl}-6- 2.65(m, 2 H), 2.80 (d, J = 10.1 Hz, 2 H), 3.15 (d, azaspiro[3.4]octane-6- J= 2.8 Hz, 2 H), 3.24-3.31 (m, 2 H), 3.37-3.43 (m, carboxylate 2 H),3.53-3.60 (m, 6 H), 3.62-3.70 (m, 1 H) 2-11 Isomer 2: ethyl 2-{4-[1- 55and m (400 MHz, DMSO-d₅) δ: 1.09-1.28 (m, 6 H), 1.40- G m/z 394 (M + H)⁺(methoxycarbonyl) 122 1.52 (m, 2 H), 1.70-1.88 (m, 8 H), 1.93-2.05 (m, 2(ES+), at 5.74 min, pyrrolidin-2-yl]piperidin- H), 2.53-2.59 (m, 3 H),2.76-2.89 (m, 1 H), 3.10- UV active 1-yl}-6- 3.31 (m, 7 H), 3.56 (s, 3H), 3.03-3.70 (m, 1 H), azaspiro[3.4]octane-6- 4.00 (q, J = 7.0 Hz, 2 H)carboxylate 2-12 Isomer 2: ethyl 2-{4-[(2S)- 55 and m (400 MHz, DMSO-d₈)δ: 1.07-1.29 (m, 6 H), 1.38- F m/z 394 (M + H)⁺ 1-(methoxycarbonyl) 1271.50 (m, 2 H), 1.50-1.63 (m, 2 H), 1.69-1.87 (m, 8 (ES+), at 1.73 min,pyrrolidin-2-yl]piperidin- H), 1.92-2.03 (m, 2 H), 2.57-2.66 (m, 1 H),2.80 UV active 1-yl}-6- (d, J = 10.4 Hz , 2 H), 3.14 (d, J = 5.8 Hz, 2H), azaspiro[3.4]octane-6- 3.27 (q, J = 6.5 Hz, 2 H), 3.38-3.43 (m, 2H), 3.56 carboxylate (s, 3 H), 3.67 (br. s., 1 H), 4.00 (q, J = 7.0 Hz,2 H) 2-13 Isomer 2: ethyl 2-{4- 55 and m (400 MHz, CD₃OD) δ: 1.24 (t, J= 7.1 Hz, 3 H), E m/z 394 (M + H)⁺ [(2R)-1- 162 1.29-1.46 (m, 2 H),1.51-1.63 (m, 2 H), 1.66-1.97 (ES+), at 4.30 min, (methoxycarbonyl) (m,11 H), 2.04-2.15 (m, 2 H), 2.73 (quin, J = 8.0 UV inactivepyrrolidin-2-yl]piperidin- Hz, 1 H), 2.93 (d, J = 11.4 Hz, 2 H), 3.25(app s, 3 1-yl}-6- H), 3.33-3.43 (m, 2 H), 3.44-3.55 (m, 1 H), 3.66azaspiro[3.4]octane-6- (s, 3 H), 3.72-3.84 (m, 1 H), 4.09 (q, J = 7.1Hz, 2 carboxylate H) 2-14 Isomer 2: ethyl 2-{4-[1- 56 and m (400MHz,DMSO-d₆) δ: 1.11-1.21 (m, 6 H), 1.38- G m/z 408 (M + H)⁺(ethoxycarbonyl) 122 1.63 (m, 6 H),1.67-1.87 (m, 9 H), 1.92-2.00 (m, 2(ES+) at 6.01 min, pyrrolidin-2-yl]piperidin- H), 2.55-2.67 (m, 2 H),2.75-2.84 (m, 2 H), 3.09- UV active 1-yl}-6- 3.22 (m, 3 H), 3.24-3.30(m, 2 H), 3.62-3.59 (m, 1 azaspiro[3.4]octane-6- H), 4.00 (m, 4 H)carboxylate 2-15 Isomer 2: methyl 2-{4- 57 and m (400 MHz, CD₃OD) δ:1.24-1.42 (m, 2 H), 1.51- E m/z 379 (M + H)⁺ (methylcarbamoyl) 157 1.64(m, 2 H), 1.67-1.98 (m, 12 H), 2.09 (dd, J = (ES+), at 2.23 min,pyrrolidin-2-yl]piperidin- 11.0, 7.6 Hz, 2 H), 2.68-2.77 (m, 4 H), 2.93(d, J = UV inactive 1-yl}-6- 11.0 Hz, 2 H), 3.22-3.26 (m, 2 H),3.35-3.41 (m, 3 azaspiro[3.4]octane-6- H), 3.66 (s, 3 H), 3.82-3.91 (m,1 H), NH not carboxylate observed 2-16 Isomer 2: ethyl 2-{4-[1- 57 and m(400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3 H), G m/z 393 (M + H)⁺(methylcarbamoyl) 122 1.37-1.47 (m, 2 H), 1.49-1.63 (m, 3 H), 1.64-1.88(ES+) at 5.46 min, pyrrolidin-2-yl]piperidin- (m, 9 H), 1.92-2.03 (m, 2H), 2.53-2.64 (m, 4 H), UV active 1-yl}-6- 2.73-2.85 (m, 2 H), 3.08-3.30(m, 7 H), 3.67-3.76 azaspiro[3.4]octane-6- (m, 1 H), 3.99 (q, J = 7.0Hz, 2 H), 5.93-6.02 (m, 1 carboxylate H) 2-17 Isomer 1: ethyl 2-{4[(2S)-57 and m (400 MHz, CD₃OD) δ: 1.25 (t, J = 7.0 Hz, 3 H), E m/z 392 (M +H)⁺ 1-methylcarbamoyl) 127 1.28-1.43 (m, 2 H), 1.49-1.64 (m, 2 H),1.66-1.95 (ES+), at 2.99 min, (pyrrolidin-2-yl]piperidin- (m, 12 H),2.06-2.15 (m, 2 H), 2.65-2.78 (m, 4 H), UV inactive 1-yl}-6- 2.93 (d, J= 11.3 Hz, 2 H), 3.21-3.29 (m, 2 H), azaspiro[3.4]octane-6- 3.33-3.33(m, 3 H), 3.82-3.89 (m, 1 H), 4.10 (q, carboxylate J = 7.0 Hz, 2 H) NHnot observed 2-17 Isomer 2: ethyl 2-{4-[(2S)- 57 and m (400 MHz, CD₃OD)δ: 1.24 (t, J = 7.1 Hz, 3 H), E m/z 393 (M + H)⁺ 1-(methylcarbamoyl) 1271.27-1.42 (m, 2 H), 1.50-1.63 (m, 2 H), 1.67-1.96 (ES+), at 3.16 min,pyrrolidin-2-yl]piperidin- (m, 12 H), 2.04-2.13 (m, 2 H), 2.66-2.78 (m,4 H), UV inactive 1-yl}-6- 2.93 (d, J = 11.3 Hz, 2 H), 3.23-3.27 (m, 2H), azaspiro[3.4]octane-6- 3.34-3.41 (m, 3 H), 3.83-3.89 (m, 1 H), 4.09(q, carboxylate J = 7.1 Hz, 2 H) 2-18 Isomer 2: ethyl 2-{4- 57 and m(400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), E m/z 393 (M + H)⁺[(2R)-1- 152 1.29-1.43 (m, 2 H), 1.50-1.65 (m, 2 H), 1.66-1.98 (ES+), at2.20 min, (methylcarbamoyl) (m, 11 H), 2.09 (dd, J = 11.1, 7.6 Hz, 2 H),2.67- UV inactive pyrrolidin-2-yl]piperidin- 2.77 (m, 4 H), 2.93 (d, J =11.0 Hz, 2 H), 3.22-3.27 1-yl}-6- (m, 4 H), 3.35-3.42 (m, 2 H),3.82-3.89 (m, 1 H), azaspiro[3.4]octane-6- 4.09 (q, J = 7.0 Hz, 2 H), NHnot observed carboxylate 2-19 Isomer 2: ethyl 2-{4-[1- 122 and q (400MHz, CDCl₃) δ: 1.16 (t, J = 7.3 Hz, 3 H), G m/z 407 (M + H)⁺(ethylcarbamoyl) 158 1.22-1.41 (m, 5 H), 1.50-1.74 (m, 4 H), 1.76-1.96(ES+) at 5.46 min, pyrrolidin-2-yl]piperidin- (m, 9 H), 1.99-2.10 (m, 2H), 2.56-2.69 (m, 1 H), UV active 1-yl}-6- 2.82-2.98 (m, 2 H), 3.18-3.47(m, 8 H), 3.86-3.97 azaspiro[3.4]octane-6- (m, 1 H), 4.06-4.25 (m, 3 H)carboxylate 2-20 Isomer 2: ethyl 2-{4-[1- 58 and m (400 MHz, DMSO-d₆)0δ: 1.08-1.15 (m, 2 H), G m/z 407 (M + H)⁺ (dimethylcarbamoyl) 122 1.16(t, J = 7.0 Hz, 3 H), 1.36-1.63 (m, 7 H), 1.70- (ES+) at 5.81 min,pyrrolidin-2-yl]piperidin- 1.88 (m, 6 H), 1.93-2.01 (m, 2 H), 2.73 (s, 6H), UV active 1-yl}-6- 2.78-2.67 (m, 2 H), 3.12-3.30 (m, 7 H), 3.87-3.95azaspiro[3.4]octane-6- (m, 1 H), 4.00 (q, J = 7.0 Hz, 2 H) carboxylate2-21 Isomer 2: ethyl 2-{4-[(2S)- 58 and m (400 MHz, DMSO-d₅) δ:1.09-1.15 (m, 2 H), 1.16 G m/z 407 (M + H)⁺ 1-(dimethylcarbamoyl) 127(t, J = 7.0 Hz, 3 H), 1.38-1.69 (m, 7 H), 1.72-1.89 (ES+) at 5.92 min,pyrrolidin-2-yl]piperidin- (m, 6 H), 1.93-2.03 (m, 2 H), 2.72 (s, 6 H),2.78- UV active 1-yl}-6- 2.82 (m, 2 H), 3.11-3.30 (m, 7 H), 3.86-3.95(m, 1 azaspiro[3.4]octane-6- H), 3.99 (q, J = 7.0 Hz, 2 H) carboxylate2-22 Isomer 2: ethyl 2-[4-(1- 122 o (400 MHz, CD₃OD) δ: 1.22-1.45 (m, 7H), 1.54- H m/z 350 (M + H)⁺ methylpyrrolidin-2- 1.87 (m, 8 H),1.88-2.01 (m, 4 H), 2.08-2.17 (m, 2 (ES+), at 6.86 min,yl)piperidin-1-yl]-6- H), 2.17-2.32 (m, 1 H), 2.35 (s, 3 H), 2.72-2.84UV active at 202 azaspiro[3.4]octane-6- (m, 1 H), 2.93-3.02 (m, 2 H),3.03-3.12 (m, 1 H), nm carboxylate 3.28 (s, 2 H), 3.37-3.46 (m, 2 H),4.11 (q, J = 7.0 Hz, 2 H) 2-23 Isomer 2: ethyl 2-{4-[1- 75 and n (400MHz, CDCl₃) δ: 1.16-1.39 (m, 4 H), 1.40- H m/z 407 (M + H)⁺ (N- 122 1.52(m, 1 H), 1.54-1.75 (m, 3 H), 1.76-2.13 (m, (ES+), at 5.77 min,methylglycyl)pyrrolidin- 12 H), 2.45 (s, 3 H), 2.56-2.71 (m, 1 H),2.82-2.97 UV inactive 2-yl]piperidin-1-yl}-6- (m, 2 H), 3.20-3.48 (m, 8H), 4.07-4.20 (m, 3 H) azaspiro[3.4]octane-6- NH not observed.carboxylate 2-24 Isomer 2: ethyl 2-{4-[1- 76 and m (400 MHz, CDCl₃) δ:1.17-1.47 (m, 5 H), 1.48- H m/z 409 (M + H)⁺ (methoxycarbamoyl) 122 2.27(m, 15 H), 2.56-2.76 (m, 1 H), 2.85-3.02 (m, (ES+), at 5.23 min,pyrrolidin-2-yl]piperidin- 2 H), 3.14-3.53 (m, 6 H), 3.74 (s, 3 H),3.91-4.03 UV active 1-yl}-6- (m, 1 H), 4.06-4.19 (m, 2 H) NH notobserved. azaspiro[3.4]octane-6- carboxylate 2-25 Isomer 2: ethyl2-{4-[(2S)- 77 and q (400 MHz, CD₃OD) δ: 1.09-1.17 (m, 6 H), 1.24 (t, Em/z 421 (M + H)⁺ 1-(propan-2- 127 J = 7.0 Hz, 3 H), 1.28-1.44 (m, 2 H),1.50-1.65 (m, (ES+), at 4.15 min, ylcarbamoyl)pyrrolidin-2- 2 H),1.66-1.99 (m, 11 H), 2.04-2.15 (m, 2 H), UV inactiveyl]piperidin-1-yl}-6- 2.68-2.79 (m, 1 H), 2.93 (d, J = 10.9 Hz, 2 H),azaspiro[3.4]octane-6- 3.22-3.28 (m, 4 H), 3.38 (q, J = 6.6 Hz, 2 H),3.85- carboxylate 3.94 (m, 2 H), 4.08 (q, J = 7.0 Hz, 2 H) NH notobserved. 2-26 Isomer 2: ethyl 2-(4-{(2S)- 78 and q (400 MHz, CD₃OD) δ:1.24 (t, J = 7.0 Hz, 3 H), E m/z 461 (M + H)⁺ 1-[(2,2,2- 127 1.29-1.43(m, 2 H), 1.48-1.65 (m, 2 H), 1.66-2.00 (ES+), at 4.03 min,trifluoroethyl)carbamoyl] (m, 11 H), 2.04-2.14 (m, 2 H), 2.67-2.79 (m, 1H), UV inactive pyrrolidin-2-yl}piperidin- 2.94 (d, J = 11.3 Hz, 2 H),3.25 (s, 3 H), 3.33-3.42 1-yl)-6- (m, 3 H), 3.53-3.78 (m, 1 H),3.85-3.98 (m, 2 H), azaspiro[3.4]octane-6- 4.09 (q, J = 7.0 Hz, 2 H) NHnot observed. carboxylate 2-27 Isomer 2: ethyl 2-{4-[(2S)- 79 and q (400MHz, DMSO-d₅) δ: 1.08-1.22 (m, 6 H), 1.38- H m/z 419 (M + H)⁺1-(azetidin-1- 127 1.89 (m, 13 H), 1.98 (br. s., 2 H), 2.07-2.20 (m, 2(ES+), at 5.88 min, ylcarbonyl)pyrrolidin-2- H), 3.03-3.31 (m, 7 H),3.67 (q, J = 7.6 Hz, 2 H), UV active at 202 yl]piperidin-1-yl}-5-3.79-3.88 (m, 1 H), 3.91-4.07 (m, 5 H) nm azaspiro[3.4]octane-6-carboxylate 2-28 Isomer 2: ethyl 2-{4-[(2S)- 80 and q (400 MHz, DMSO-d₅)δ: 1.02-1.19 (m, 5 H), 1.33- E m/z 449 (M + H)⁺ 1-(morpholin-4- 127 1.61(m, 2.62 (m, 1 H), 2.75 (d, J = 9.8 Hz, 2 H), (ES+), at 3.29 min,ylcarbonyl)pyrrolidin-2- 2.96-3.06 (m, 2 H), 3.08-3.28 (m, 7 H),3.44-3.61 UV inactive yl]piperidin-1-yl}-6- (m, 4H), 3.87-4.00 (m, 3 H),4.05-4.13 (m, 1 H) azaspiro[3.4]octane-6- carboxylate 2-29 Isomer 2:ethyl 2-{4-[(2S)- 81 and q (400 MHz, DMSO-d₅) δ: 0.28-0.40 (m, 2 H),0.43- E m/z 419 (M + H)⁺ 1-(cyclopropylcarbamoyl) 127 0.53 (m, 2 H),1.02-1.24 (m, 5 H), 1.39 (t, J = 11.3 (ES+), at 3.24 min,pyrrolidin-2-yl]piperidin- Hz, 2 H), 1.43-1.58 (m, 2 H), 1.58-1.85 (m, 6H), UV inactive 1-yl}-6- 1.94 (t, J = 9.2 Hz, 2 H), 2.52-2.61 (m, 1 H),2.76 azaspiro[3.4]octane-6- (d, J = 11.3 Hz, 2 H), 3.07-3.19 (m, 7 H),3.19- carboxylate 3.28 (m, 1 H), 3.66-3.76 (m, 1 H), 3.97 (q, J = 7.0Hz, 2 H), 4.04-4.15 (m, 2 H), 6.09 (d, J = 2.7 Hz, 1 H) 2-30 Isomer 2:ethyl 2-{4-[(2S)- 82 and q (400 MHz, DMSO-d₅) δ: 1.02-1.22 (m, 5 H),1.20- E m/z 433 (M + H)⁺ 1-(cyclobutylcarbamoyl) 127 1.57 (m, 6 H),1.58-1.98 (m, 10 H), 1.99-2.12 (m, (ES+), at 3.65 min,pyrrolidin-2-yl]piperidin- 2 H), 2.51-2.60 (m, 1 H), 2.75 (d, J = 10.5Hz, 2 UV inactive 1-yl}-6- H), 3.07-3.27 (m, 8 H), 3.71 (br. s., 1 H),3.97 (q, azaspiro[3.4]octane-6- J = 7.0 Hz, 2 H), 4.04-4.15 (m, 2 H),6.13 d, J = carboxylate 8.2 Hz, 1 H) 2-31 Isomer 2: ethyl 2-(4-{(2S)- 83and q (400 MHz, DMSO-d₅) δ: 1.01-1.26 (m, 5 H), 1.32- E m/z 437 (M + H)⁺methoxyethyl)carbamoyl] 127 1.58 (m, 5 H) 1.59-1.86 (m, 8 H), 1.94 (t, J= 9.2 (ES+), at 3.06 min, pyrrolidin-2-yl}piperidin- Hz, 2 H), 2.52-2.61(m, 1 H), 2.76 (d, J = 10.5 Hz, UV inactive 1-yl)-6- 2 H), 3.02-3.28 (m,13 H), 3.64-3.74 (m, 1 H), azaspiro[3.4]octane-6- 3.97 (q, J = 7.0 Hz, 2H) 6.01 (l, J = 5.5 Hz, 1 H) carboxylate 2-32 Isomer 2: ethyl2-(4-[(2S)- 84 and q (400 MHz, DMSO-d₅) δ: 1.01-1.18 (m, 5 H), 1.32- Em/z 433 (M +H)⁺ 1-(pyrrolidin-1- 127 1.86 (m, 17 H), 1.93 (t, J = 9.2Hz, 2 H), 2.52-2.61 (ES+), at 3.85 min, ylcarbonyl)pyrrolidin-2- (m, 1H), 2.75 (d, J = 9.0 Hz, 2 H), 3.02-3.30 (m, 9 UV inactiveyl]piperidin-1-yl}-6- H), 3.84-3.92 (m, 1 H), 3.97 (q, J = 7.0 Hz, 2 H),azaspiro[3.4]octane-6- 4.06-4.12 (m, 1 H) carboxylate 2-33 Isomer 1:ethyl 2-{4-[(2S)- 76 and q (400 MHz, CDCl₃) δ: 1.03-1.45 (m, 5 H), 1.47-I m/z 40.9 (M + H)⁺ 1-(methoxycarbamoyl) 127 2.24 (m, 16 H), 2.56-2.77(m, 1 H), 2.92 (br, s., 2 (ES+), at 3.50 min, pyrrolidin-2-yl]piperidin-H), 3.14-3.53 (m, 5 H), 3.75 (s, 3 H), 3.89-4.04 UV active at 1-yl}-6-(m, 1 H), 4.12 (q, J = 6.6 Hz, 2 H) NH not azaspiro[3.4]octane-8-observed, 202 nm carboxylate 2-33 Isomer 2: ethyl 2-{4-[(2S)- 76 and q(400 MHz, CDCl₃) δ: 1.27 (t, J = 8.50 Hz, 3 H), I m/z 409 (M + H)⁺1-(methoxycarbamoyl) 127 1.36-2.22 (m, 17 H), 2.76 (br. s., 1 H),2.93-3.10 (ES+), at 3.64 min, pyrrolidin-2-yl]piperidin- (m, 2 H),3.16-3.26 (m, 1 H), 3.28-3.48 (m, 5 H), UV active at 202 1-yl}-6- 3.74(s, 3 H), 3.99 (d. J = 5.49 Hz, 1 H), 4.14 (q, nm azaspiro[3.4]octane-6-J = 6.50 Hz, 2 H) NH not observed. carboxylate 2-34 Isomer 1: ethyl2-(4-{(2S)- 85 and q (400 MHz, CDCl₃) δ: 1.15-1.48 (m, 8 H), 1.56- I m/z423 (M + H)⁺ 1-[methoxy(methyl) 127 2.07 (m, 11 H), 2.09-2.39 (m, 5 H),2.95-3.11 (m, (ES+), at 4.17 min, carbamoyl)pyrrolidin- 3 H), 3.19-3.54(m, 6 H), 3.57-3.73 (m, 3 H), 4.04- UV active at 202 2-yl}piperidin-1-4.20 (m, 2 H) nm yl)-6-azaspiro[3.4]octane- 6-carboxylate 2-34 Isomer 2:ethyl 2-(4-{(2S)- 85 and q (400 MHz, CDCl₃) δ: 1.19-1.37 (m, 7 H), 1.53-I m/z 423 (M + H)⁺ 1-[methoxy(methyl) 127 2.01 (m, 12 H), 2.10-2.27 (m,2 H), 2.99 (s, 3 H), (ES+), at 4.30 min, carbamoyl)pyrrolidin- 3.29-3.45(m, 6 H), 3.46-3.54 (m, 1 H), 3.59-3.67 UV active at 2022-yl}piperidin-1- (m, 3 H), 4.07-4.21 (m, 4 H) nmyl)-6-azaspiro[3.4]octane- 6-carboxylate 2-35 Isomer 2: ethyl2-(4-{(2S)- 86 and q (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), Em/z 447 (M + H)⁺ 1-[(1-methylcyclobutyl) 127 1.28-1.39 (m, 2 H), 1.43(s, 3 H), 1.49-2.02 (m, 17 (ES+), at 4.06 min, carbamoyl]pyrrolidin-2-H), 2.03-2.14 (m, 2 H), 2.15-2.32 (m, 2 H), 2.73 UV inactiveyl}piperidin-1-yl)-6- (quin, J = 7.8 Hz, 1 H), 2.93 (d, J = 11.3 Hz, 2H), azaspiro[3.4]octane-6- 3.20-3.28 (m, 3 H), 3.33-3.44 (m, 3 H),3.81-3.91 carboxylate (m, 1 H), 4.09 (q, J = 7.0 Hz, 2 H) NH notobserved. 2-36 Isomer 2: ethyl 2-(4-{(2S)- 87 and q (400 MHz, CD₃OD) δ:1.24 (t, J = 7.1 Hz, 3 H), E m/z 449 (M + H)⁺ 1-[(3-methyloxelan-3- 1271.28-1.44 (m, 2 H), 1.50-1.55 (m, 5 H), 1.66-1.98 (ES+), at 3.09 min,yl)carbamoyl]pyrrolidin-2- (m, 11 H), 2.04-2.14 (m, 2 H), 2.67-2.79 (m,1 H), UV inactive yl}piperidin-1-yl)-6- 2.93 (d, J = 11.3 Hz, 2 H),3.21-3.27 (m, 3 H), azaspiro[3.4]octane-6- 3.33-3.42 (m, 3 H), 3.81-3.89(m, 1 H), 4.09 (q, carboxylate J = 7.1 Hz, 2 H), 4.38 (d, J = 7.0 Hz, 2H), 4.72 (dd, J = 14.8 7.0 Hz, 2 H) NH not observed. 2-37 Isomer 2:ethyl 2-(4-{(2S)- 88 and q (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3H), E m/z 459 (M + H)⁺ 1-[(3,3-difluoropyrrolidin- 127 1.27-1.40 (m, 2H), 1.51-1.30 (m, 7 H), 1.81-1.98 (ES+), at 2.44 min,1-yl)carbonylipyrrolidin- (m, 6 H), 2.05-2.14 (m, 2 H), 2 28-2.45 (m, 2H), UV inactive 2-yl}piperidin-1-yl)-6- 2.73 (quin, J = 7.9 Hz, 1 H),2.03 (d, J = 10.9 Hz, 2 azaspiro[3.4]octane-6- H), 3.25 (s, 3 H),3.34-3.43 (m, 3 H), 3.43-3.57 carboxylate (m, 2 H), 3.68-3.77 (m, 1 H),3.82-3.97 (m, 1 H), 4.00-4.13 (m, 3 H) 2-38 Isomer 2: ethyl 2-(4-{(2S)-89 and q (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), E m/z 469 (M +H)⁺ 1-[(3,3- 127 1.27-1.44 (m, 2 H), 1.49-1.64 (m, 2 H), 1.65-2.00(ES+), at 2.83 min, difluorocyclobutyl) (m, 12 H), 2.02-2.14 (m, 2 H),2.46-2.63 (m, 2 H), UV inactive carbamoyl]pyrrolidin-2- 2.73 (quin, J =7.9 Hz , 1 H), 2.78-2.89 (m, 2 H), yl}piperidin-1-yl)-6- 2.93 (d, J =11.7 Hz, 2 H), 3.22-3.28 (m, 2 H), azaspiro[3.4]octane-6- 3.34-3.42 (m,3 H), 3.84-3.92 (m, 1 H), 4.00-4.13 carboxylate (m, 3 H) NH notobserved. 2-39 Isomer 2: ethyl 2-(4-{(2S)- 90 and q (400 MHz, CD₃OD) δ:1.24 (t, J = 7.0 Hz, 3 H), E m/z 455 (M + H)⁺1-[(3,3-difluoroazetidin-1- 127 1.27-1.40 (m, 2 H), 1.52-1.66 (m, 2 H),1.67-1.98 (ES+), at 2.83 min, yl)carbonyl]pyrrolidin-2- (m, 11 H),2.04-2.14 (m, 2 H), 2.74 (quin, J = 8.0 UV inactiveyl}piperidin-1-yl)-6- Hz, 1 H), 2.93 (d, J = 10.9 Hz, 2 H), 3.16-3.27(m, azaspiro[3.4]octane-6- 3 H), 3.34-3.43 (m, 3 H), 3.99 (q, J = 6.1Hz, 1 H), carboxylate 4.04-4.22 (m, 4 H), 4.36-4.49 (m, 2H) 2-40 Isomer2: methyl 2-(4- 78 and q (400 MHz, CD₃OD) δ: 1.26-1.44 (m, 2 H), 1.49- Em/z 447 (M + H)⁺ {(2S)-1-[(2,2,2- 127 1.65 (m, 2 H), 1.66-1.99 (m, 12H), 2.04-2.14 (m, (ES+), at 2.45 min, trifluoroethyl)carbamoyl] 2 H),2.67-2.82 (m, 1 H), 2.94 (d, J = 10.9 Hz, 2 UV inactivepyrrolidin-2-yl}piperidin- H), 3.17-3.27 (m, 3 H), 3.35-3.43 (m, 2 H),3.63- 1-yl)-6- 3.78 (m, 4 H), 3.85-4.00 (m, 2 H) NH notazaspiro[3.4]octane-6- observed. carboxylate 2-41 Isomer 2: methyl 2-(4-90 and q (400 MHz, CD₃OD) δ: 1.26-1.42 (m, 2 H), 1.52- E m/z 441 ((M +H)⁺ ((2S)-1-[(3,3- 157 1.66 (m, 2 H), 1.68-1.99 (m, 11 H), 2.04-2.15 (m,(ES+), at 2.22 min, difluoroazetidin-1- 2 H), 2.73 (quin, J = 7.9 Hz, 1H), 2.93 (d, J = 10.9 UV inactive yl)carbonyl]pyrrolidin-2- Hz, 2 H),3.17-3.28 (m, 3 H), 3.34-3.44 (m, 3 H), yl}piperidin-1-yl)-6- 3.67 (s, 3H), 3.94-4.04 (m, 1 H), 4.09-4.24 (m, 2 azaspiro[3.4]octane-6- H),4.36-4.51 (m, 2 H) carboxylate 2-42 Isomer 1: ethyl 2-(4-{(2S)- 91 and r(400 MHz, CD₃OD) δ: 1.02-1.12 (m, 6 H), 1.17- E m/z 449 (M + H)⁺1-[ethyl(propan-2- 127 1.26 (m, 6 H), 1.28-1.40 (m, 2 H), 1.49-1.98 (m,(ES+), at 3.42 min, yl)carbamoyl]pyrrolidin-2- 15 H), 2.05-2.15 (m, 3H), 2.67-2.79 (m, 2 H), UV inactive yl}pipendin-1-yl)-6- 2.85-2.96 (m, 3H), 3.33-3.41 (m, 3 H), 3.88-4.00 azaspiro[3.4]octane-6- (m, 1 H),4.02-4.15 (m, 3 H) carboxylate 2-42 Isomer 2: ethyl 2-(4-{(2S)- 91 and r(400 MHz, CD₃OD) δ: 1.00-1.12 (m, 6 H), 1.18- E m/z 449 (M + H)⁺1-[ethyl(propan-2- 127 1.27 (m, 6 H), 1.27-1.43 (m, 3 H), 1.43-1.99 (m,(ES+), at 3.61 min, yl)carbamoyl]pyrrolidin-2- 13 H), 2.04-2.14 (m, 2H), 2.68-2.78 (m, 1 H), UV inactive yl}piperidin-1-yl)-6- 2.85-2.98 (m,3 H), 3.25 (br. s., 3 H), 3.37 (t, J = azaspiro[3.4]octane-6- 6.8 Hz, 3H), 3.88-4.00 (m, 1 H), 4.01-4.13 (m, carboxylate 3 H) 2-43 Isomer 2:ethyl 2-(4-{(2S)- 92 and m 400 MHz, CDCl₃) δ: 0.78-0.95 (m, 5 H),1.20-1.42 I m/z 434 (M + H)⁺ 1-[(cyclobutyloxy) 127 (m, 6 H), 1.49-2.17(m, 15 H), 2.28-2.43 (m, 2 H), (ES+), at 5.19 min, carbonyl]pyrrolidin-2.57-2.71 (m, 1 H), 2.83-3.00 (m, 2 H), 3.19-3.61 UV active at 2022-yl}piperidin-1-yl)- (m, 4 H), 3.72-3.88 (m, 1 H), 4.13 (q, J = 7.02Hz, nm 6-azaspiro[3.4]octane-6- 2 H), 4.88-5.04 (m, 1 H) carboxylate2-44 Isomer 2: ethyl 2-(4-{(2S)- 93 and q (400 MHz, CD₃OD) δ: 1.24 (t, J= 7.0 Hz, 3 H), E m/z 425 (M + H)⁺ 1-[(2-fluoroethyl) 127 1.28-1.45 (m,2 H), 1.58 (t, J = 15.6 Hz, 2 H), (ES+), at 3.24 min,carbamoyl]pyrrolidin- 1.67-1.99 (m, 12 H), 2.04 -2.15 (m, 2 H), 2.73 UVinactive 2-yl}piperidin-1-yl)-6- (quin, J = 7.9 Hz, 1 H), 2.93 (d, J =11.3 Hz, 2 H), azaspiro[3.4]octane-6- 3.25 (s, 2 H), 3.33-3.53 (m, 5 H),3.84-3.92 (m, 1 carboxylate H), 4.09 (q, J = 7.0 Hz, 2 H), 4.35 (t, J =5.2 Hz, 1 H), 4.47 (t, J = 5.2 Hz, 1 H) NH not observed. 2-45 Isomer 2:ethyl 2-(4-{(2S)- 94 and q (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3H), E m/z 443 (M + H)⁺ 1-[(2,2-difluoroethyl) 127 1.28-1.44 (m, 2 H),1.50-1.64 (m, 2 H), 1.65-2.01 (ES+), at 3.45 min, carbamoyl]pyrrolidin-(m, 12 H), 2.02-2.15 (m, 2 H), 2.73 (quin, J = 7.6 UV inactive2-yl)piperidin-1-yl)-6- Hz, 1 H), 2.93 (d, J = 11.3 Hz, 2 H), 3.25 (s, 3H), azaspiro[3.4]octane-6- 3.33-3.60 (m, 4 H), 3.88 (d, J = 5.1 Hz, 1H), 4.09 carboxylate (q, J = 7.0 Hz, 2 H), 5.66-6.01 (m, 1 H) NH notobserved. 2-46 Isomer 2: ethyl 2-{4-[(2S)- 95 and m (400 MHz, CDCl₃) δ:1.15-1.29 (m, 3 H), 1.30- I m/z 408 (M + H)⁺ 1-(methoxyacetyl) 127 1.52(m, 4 H), 1.51-1.98 (m, 12 H), 2.00-2.15 (m, (ES+), at 3.58 min,pyrrolidin-2-yl]pipendin- 3 H), 2.56-2.74 (m, 1 H), 2.80-3.00 (m, 2 H),3.12- UV active 1-yl}-6- 3.53 (m, 8 H), 3.94-4.20 (m, 4 H)azaspiro[3.4]octane-6- carboxylate 2-47 Isomer 2: ethyl 2-(4-{(2S)- 96and s (400 MHz, CDCl₃) δ: 1.16-1.49 (m, 5 H), 1.50- I m/z 426 (M + H)⁺1-[(2-fluoroethoxy) 127 2.17 (m, 17 H), 2.83-3.05 (m, 1 H), 3.16-3.64(m, (ES+), at 4.50 min, carbonyl]pyrrolidin- 6 H), 3.78-3.94 (m, 1 H),4.13 (q, J = 6.5 Hz, 2 H), UV active at 202 2-yl)pipendin-1-yl)-6-4.24-4.48 (m, 2 H), 4.52-4.76 (m, 2 H) nm azaspiro[3.4]octane-6-carboxylate 2-48 Isomer 2: ethyl 2-(4-{(2S)- 97 and s (400 MHz, CDCl₃)δ: 1.17-1.47 (m, 5 H), 1.49- I m/z 462 (M + H)⁺ 1-[(2,2,2- 127 2.33 (m,15 H), 2.66 (d, J = 7.32 Hz, 1 H), 2.84- (ES+), at 5.07 min,trifluoroethoxy)carbonyl] 3.09 (m, 2 H), 3.19-3.46 (m, 5 H), 3.47-3.71(m, 1 UV active at 202 pyrrolidin-2-yl}piperidin- H), 3.84 (dd, J =18.16, 4.4 Hz, 1 H), 4.11 (q, J = nm 1-yl)-6- 7.0 Hz, 2 H), 4.32-4.67(m, 2 H) azaspiro[3.4]octane-6- carboxylate 2-49 Isomer 2: ethyl2-(4-{(2S)- 98 and s (400 MHz, CDCl₃) δ: 1.15-1.45 (m, 5 H), 1.46- I m/z410 (M + H)⁺ 1-[(methylsultanyl) 127 1.76 (m, 9 H), 1.79-2.13 (m, 9 H),2.35 (s, 3 H), (ES+), at 4.74 min, carbonyl]pyrrolidin- 2.58-2.72 (m, 1H), 2.85-3.0.2 (m, 2 H), 3.21-3.57 UV active at 2.022-yl}piperidin-1-yl)- (m, 4 H), 4.13 (q, J = 6.8 Hz, 2 H) nm6-azaspiro[3.4]octane-6- carboxylate 2-50 Isomer 2: ethyl 2-(4-{(2S)- 99and m (400 MHz, CDCl₃) δ: 1.17-1.31 (m, 3 H), 1.35- I m/z 436 (M + H)⁺1-[(2-methoxyethoxy) 127 1.51 (m, 2 H), 1.52-2.17 (m, 18 H), 2.90-3.14(m, (ES+), at 4.83 min, carbonyl]pyrrolidin- 2 H), 3.21-3.47 (m, 7 H),3.48-3.65 (m, 2 H), 3.76- UV active at 202 2-yl}piperidin-1-yl)- 3.91(m, 1 H), 4.13 (q, J = 6.8 Hz, 2 H), 4.18-4.33 nm6-azaspiro[3.4]octane-6- (m, 2 H) carboxylate 2-51 Isomer 2: ethyl2-{4-[(2S)- 100 and m (400 MHz, CDCl₃) δ: 1.15-1.49 (m, 6 H), 1.51- Im/z 451 (M + H)⁺ 1-{[2-(dimethylamino) 127 2.16 (m, 14 H), 2.32 (s, 6H), 2.52-2.80 (m, 3 H), (ES+), at 4.22 min, ethoxy]carbonyl} 2.85-3.05(m, 2 H), 3.14-3.63 (m, 7 H), 4.07-4.27 UV active at 202pyrrolidin-2-yl]piperidin- (m, 4 H) nm 1-yl}-6- azaspiro[3.4]octane-6-carboxylate 2-52 Isomer 2: ethyl 2-{4-[(2S)- 101 and t (400 MHz, CDCl₃)δ: 1.14-1.51 (m, 7 H), 1.52- I m/z 394 (M + H)⁺ 1-(hydroxyacetyl) 1271.77 (m, 3 H), 1.77-2.21 (m, 10 H), 2.62 (d, J = (ES+), at 3.66 min,pyrrolidin-2-yl]piperidin- 10.1 Hz, 1 H), 2.90 (d, J = 10.1 Hz, 2 H),3.16- UV active at 202 1-yl}-6- 3.69 (m, 7 H), 3.98-4.28 (m, 4 H) OH notnm azaspiro[3.4]octane-6- observed. carboxylate 2-53 Isomer 2: ethyl2-{4-[(2S)- 102 and u (400 MHz, CD₃OD) δ: 1.21-1.36 (m, 4 H), 1.44- Im/z 446 (M + H)⁺ 1-(3,3,3- 127 1.66 (m, 2 H), 1.77 (d, J = 12.8 Hz, 2H), 1.85-2.08 (ES+), at 4.42 min, trifluoropropanoyl) (m, 8 H),2.10-2.23 (m, 2 H), 2.23-2.32 (m, 2 H), UV active at 202pyrrolidin-2-yl]piperidin- 2.39 (br. s., 2 H), 3.25-3.31 (m, 2 H),3.38-3.70 nm 1-yl}-6- (m, 7 H), 4.06-4.17 (m, 3 H)azaspiro[3.4]octane-6- carboxylate 2-54 Isomer 1: ethyl 2-(4-{(2S) 103and q (400 MHz, CD₃OD) δ: 1.20-1.28 (m, 3 H), 1.29- E m/z 470 (M + H)⁺1-[(pyridin-2- 127 1.47 (m, 2 H), 1.60 (t, J = 12.3 Hz, 2 H), 1.67-2.03(ES+), at 2.99 min, ylmethyl)carbamoyl] (m, 12 H), 2.04-2.18 (m, 2 H),2.65-2.79 (m, 1 H), UV inactive pyrrolidin-2-yl}piperidin- 2.94 (d, J =9.0 Hz, 2 H), 3.33-3.51 (m, 5 H), 3.91 1-yl)-6- (q, J = 5.5 Hz, 1 H),4.10 (q, J = 7.2 Hz, 2 H), azaspiro[3.4]octane-6- 4.36-4.55 (m, 2 H),7.28 (dd, J = 7.4, 5.1 Hz, 1 H), carboxylate 7.38 (d, J = 7.4 Hz, 1 H),7.79 (ddd, J = 7.4, 1.6 Hz, 1 H), 8.45 (d, J = 5.1 Hz, 1 H) NH notobserved. 2-54 Isomer 2: ethyl 2-(4-{(2S)- 103 and q (400 MHz, CD₃OD) δ:1.24 (t, J = 7.0 Hz, 3 H), E m/z 470 (M + H)⁺ 1-[(pyridin-2-ylmethyl)127 1.28-1.46 (m, 2 H), 1.60 (t, J = 12.3 Hz, 1 H), (ES+), at 3.17 min,carbamoyl]pyrrolidin- 1.67-2.02 (m, 11 H), 2.09 (t, J = 9.6 Hz, 2 H),2.73 UV inactive 2-yl}piperidin-1-yl)-6- (quin, J = 7.9 Hz, 1 H), 2.94(d, J = 8.6 Hz, 2 H), azaspiro[3.4]octane-6- 3.25 (s, 2 H), 3.33-3.52(m, 5 H), 3.91 (d, J = 5.5 carboxylate Hz, 1 H), 4.03-4.14 (m, 2 H),4.36-4.55 (m, 2 H), 7.28 (dd, J = 7.5, 5.27 Hz, 1 H), 7.38 (d, J = 7.6Hz, 1 H), 7.79 (ddd, J = 7.6, 1.6 Hz, 1 H), 8.45 (d, J = 5.3 Hz, 1 H) NHnot observed. 2-55 Isomer 1, ethyl 2-(4-{(2S)- 104 and q (400 MHz,CD₃OD) δ: 1.16-1.28 (m, 3 H), 1.29- E m/z 475 (M + H)⁺ 1-[methyl(2,2,2-127 1.49 (m, 2 Hz, 2 H), 2.65-2.79 (m, 1 H), 2.87-2.98 (ES+), at 4.02min, trifluoroethyl)carbamoyl] (m, 2 H), 3.01-3.16 (m, 3 H), 3.25 (s, 1H), 3.33- UV inactive pyrrolidin-2-yl)piperidin- 3.51 (m, 5 H),3.96-4.18 (m, 3 H), 4.47-4.70 (m, 1 1-yl)-6- H) azaspiro[3.4]octane-6-carboxylate 2-55 Isomer 2: ethyl 2-(4-{(2S)- 104 and q (400 MHz, CD₃OD)δ: 1.24 (t, J = 7.2 Hz, 3 H), E m/z 475 (M + H)⁺ 1-[methyl(2,2,2- 1271.28-1.42 (m, 2 H), 1.51-1.80 (m, 6 H), 1.82-2.03 (ES+), at 4.17 min,trifluoroethyl)carbamoyl] (m, 6 H), 2.09 (t, J = 9.8 Hz, 2 H), 2.66-2.79(m, 1 UV inactive pyrrolidin-2-yl}pipendin- H), 2.93 (d, J = 9.8 Hz, 2H), 3.04 (s, 3 H) 3.25 (s, 1-yl)-6- 2 H), 3.33-3.50 (m, 6 H), 4.01-4.15(m, 3 H), 4.53- azaspiro[3.4]octane-6- 4.68 (m, 1 H) carboxylate 2-56Isomer 2: ethyl 2-{4-[(2S)- 105 and q (400 MHz, CD₃OD) δ: 1.24 (t, J =7.0 Hz, 3 H), E m/z 435 (M + H)⁺ 1-(oxetan-3- 127 1.27-1.42 (m, 2 H),1.48-1.64 (m, 2 H), 1.66-1.99 (ES+), at 2.82 min,ylcarbamoyl)pyrrolidin-2- (m, 11 H), 2.02-2.14 (m, 2 H), 2.72 (quin, J =7.9 UV inactive yl]piperidin-1-yl}-6- Hz, 1 H), 2.93 (d, J = 11.3 Hz, 2H), 3.25 (s, 2 H), azaspire[3.4]octane-6- 3.33-3.43 (m, 4 H), 3.89 (q, J= 5.3 Hz, 1 H), 4.08 carboxylate (q, J = 7.0 Hz, 2 H), 4.55-4.63 (m, 2H), 4.78-4.86 (m, 3 H) NH not observed. 2-57 Isomer 2: ethyl 2-(4-{(2S)-106 and q (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.2 Hz, 3 H), E m/z 449 (M +H)⁺ 1-[methyl(oxelan-3- 127 1.27-1.43 (m, 2 H), 1.48-1.79 (m, 7 H),1.81-2.00 (ES+), at 3.20 min, yl)carbamoyl]pyrrolidin-2- (m, 7 H),2.03-2.15 (m, 2 H), 2.72 (quin, J = 7.8 UV inactiveyl]piperidin-l-yl)-6- Hz, 1 H), 2.81-2.99 (m, 4 H), 3.25 (s, 2 H), 3.33-azaspiro[3.4]octane-8- 3.45 (m, 4 H), 3.97-4.13 (m, 3 H), 4.56-4.84 (m,5 carboxylate H) NH not observed. 2-58 Isomer 2: ethyl 2-{4-[(2S)-Example v (400 MHz, CD₃OD) δ: 1.18-1.32 (m, 6 H), 1.36- E m/z 408 (M +H)⁺ 1-propanethioylpyrrolidin- 2-7 and 1.62 (m, 4 H), 1.62-1.82 (m, 2H), 1.83-2.16 (m, (ES+), at 3.82 min, 2-yl]piperidin-1-yl}-6- 107 10 H),2.54 (br. s., 1 H), 2.65-2.82 (m, 3 H), 2.93 UV inactiveazaspiro[3.4]octane-6- (d, J = 10.9 Hz, 2 H), 3.25 (s, 2 H), 3.38 (q, J= 6.6 carboxylate Hz, 2 H), 3.56-3.67 (m, 1 H), 3.75-3.86 (m, 1 H), 4.09(q, J = 7.0 Hz, 2 H), 4.62-4.73 (m, 1 H) 2-59 Isomer 2: ethyl 2-{4- 2,54 ap and (400 MHz, CD₃OD) δ: 1.05-1.15 (m, 3 H), 1.24 (t, E m/z 410(M + H)⁺ [(2S,4S)-4-fluoro-1- and 112 m J = 7.0 Hz, 3 H), 1.27-1.51 (m,2 H), 1.52-1.97 (m, (ES+), at 3.32 min, propanoylpyrrolidin-2- 9 H),1.98-2.27 (m, 4 H), 2.27-2.48 (m, 2 H), 2.66- UV inactiveyl]piperidin-1-yl}-6- 2.79 (m, 1 H), 2.87-3.01 (m, 2 H), 3.25 (s, 2 H),azaspiro[3.4]octane-6- 3.34-3.45 (m, 2 H), 3.61-3.75 (m, 1 H), 3.83-4.00carboxylate (m, 1 H), 4.03-4.21 (m, 3 H), 5.19-5.40 (m, 1 H) 2-60 Isomer2: ethyl 2-{4-[(2S)- 2, 54 ap and (400 MHz, CD₃OD) δ: 1.04-1.16 (m, 3H), 1.24 (t, E m/z 428 (M + H)⁺ 4,4-difluoro-1- and 113 m J = 7.1 Hz, 3H), 1.27-1.43 (m, 3 H), 1.51-1.82 (m, (ES+), at 3.52 min,propanoylpyrrolidin-2- 4 H), 1.83-2.01 (m, 5 H), 2.04-2.15 (m, 2 H),2.23- UV inactive yl]piperidin-1-yl}-6- 2.54 (m, 4 H), 2.67-2.80 (m, 1H), 2.87-3.02 (m, 2 azaspiro[3.4]octane-6- H), 3.25 (s, 2 H), 3.38 (q, J= 6.6 Hz, 2 H), 3.71- carboxylate 4.05 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2H), 4.14-4.36 (m, 1 H) 2-61 Isomer 2: ethyl 2-{4-[(2S)- 114 and w (400MHz, DMSO-d₅) δ: 0.99 (t, J = 7.2 Hz, 3 H), K m/z 364 (M + H)⁺1-ethylpyrrolidin-2- 127 1.06-1.26 (m, 5 H), 1.30-1.41 (m, 1 H),1.42-1.66 (ES+), at 5.60 min, yl]piperidin-1-yl}-6- (m, 7 H), 1.67-1.89(m, 4 H), 1.90-2.10 (m, 4 H), UV active at 202 azaspiro[3.4]octane-6-2.13-2.22 (m, 1 H), 2.55-2.64 (m, 1 H) 2.65-2.85 nm carboxylate (m, 3H), 3.02 (t, J = 7.5 Hz, 1 H), 3.14 (d, J = 6.1 Hz, 2 H), 3.27 (q, J =6.8 Hz, 2 H), 3.54-3.67(m, 1 H), 4.00 (q, J = 7.2 Hz, 2 H) 2-62 Isomer2: ethyl 2-(4-{(2S)- 116 and x (400 MHz, CD₃OD) δ: 1.17-1.42 (m, 5 H),1.43- E m/z 469 (M + H)⁺ 1-[3-(pyridin-2- 127 1.59 (m, 2 H), 1.60-1.98(m, 11 H), 2.08 (t, J = 9.5 (ES+), at 3.32 min,yl)propanoyl]pyrrolidin-2- Hz, 2 H), 2.65-2.97 (m, 5 H), 3.01-3.17 (m, 2H), UV inactive yl}piperidin-1-yl)-6- 3.17-3.28 (m, 2 H), 3.38 (q, J =6.6 Hz, 3 H), 3.49- azaspiro[3.4]octane-6- 3.65 (m, 1 H), 3.96-4.04 (m,1 H), 4.09 (q, J = 7.2 carboxylate Hz, 2 H), 7.21-7.28 (m, 1 H),7.30-7.36 (m, 1 H), 7.73 (ddd, J = 7.6, 1.6 Hz, 1 H), 8.40-8.48 (m, 1 H)2-63 Isomer 2: ethyl 2-(4-{(2S)- 117 and q (400 MHz, CD₃OD) δ: 1.24 (t,J = 7.0 Hz, 3 H), E m/z 484 (M + H)⁺ 1-[methyl(pyridin-2- 127 1.27-1.42(m, 2 H), 1.51 (d, J = 11.7 Hz, 1 H), (ES+), at 3.72 min,ylmethyl)carbamoyl] 1.57-1.80 (m, 6 H), 1.82-2.02 (m, 7 H), 2.04-2.14 UVinactive pyrrolidin-2-yl}piperidin- (m, 2 H), 2.73 (quin, J = 7.9 Hz, 1H), 2.84-2.97 1-yl)-6-azaspiro[3.4]octane- (m, 5 H), 3.25 (s, 2 H), 3.38(q, J = 6.6 Hz, 2 H), 6-carboxylate 3.47 (t, J = 7.8 Hz, 1 H), 4.09 (q,J = 7.0 Hz, 3 H), 4.42 (d, J = 16.4 Hz, 1 H), 4.64 (d, J = 16.4 Hz, 1H), 7.31 (dd, J = 7.2, 5.00 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.82(dd, J = 7.8, 7.20 Hz, 1 H), 8.49 (d, J = 5.0 Hz, 1 H) 2-64 Isomer 2:ethyl 2-(4-{(2S)- 118 and q (300 MHz, CD₃OD) δ: 1.20-1.47 (m, 5 H),1.50- E m/z 471 (M + H)⁺ 1-[(pyridin-2-ylmethoxy) 127 2.02 (m, 12 H),2.04-2.19 (m, 2 H), 2.66-2.82 (m, (ES+), at 3.69 min,carbonyl]pyrrolidin- 1 H), 2.94 (d, J = 10.4 Hz, 2 H), 3.26 (s, 2 H), UVinactive 2-yl}piperidin-1-yl)-6- 3.37-3.46 (m, 3 H), 3.51-3.68 (m, 1 H),3.79-3.95 azaspiro[3.4]octane-6- (m, 1 H), 3.99-4.19 (m, 3 H), 5.20 (s,2 H), 7.31- carboxylate 7.41 (m, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.87(dd, J = 7.8, 7.7 Hz, 1 H), 8.47-8.57 (m, 1 H) 2-65 Isomer 2: ethyl2-{4-[(2S)- 127, 222 y (400 MHz, CDCl₃) δ: 1.25 (t, J = 8.2 Hz, 3H), Im/z 541 (M + H)⁺ 1-(N- and 226 1.34-1.48 (m, 4H), 1.52-2.21 (m, 9H),2.37-2.71 (ES+), at 4.51 min, [(benzyloxy)carbonyl]-β- (m, 4H),2.91-3.05 (m, 3H), 3.19-3.59 (m, 9H), UV active alanyl}pyrrolidin-2-4.04-4.19 (m, 4H), 5.10 (s, 2H), 5.64 (s, 1H), 7.28-yl]piperidin-1-yl}-6- 7.42 (m, 5H). azaspiro[3.4]octane-6- carboxylate2-66 Isomer 2: ethyl 2-{4-[(2S)- 127, 222 y (400 MHz, DMSO-d₆) δ:1.14-1.26 (m, 6H), 1.35- I m/z 407 (M + H)⁺ 1-(β-alanyl)pyrrolidin-2-and 226 1.63 (m, 4H), 1.65-1.88 (m, 9H), 1.97-1.99 (m, (ES+), at 3.70min, yl]piperidin-1-yl}-6- 2H), 2.32-2.69 (m, 4H), 2.76-2.83 (m, 3H),3.08- UV inactive azaspiro[3.4]octane-6- 3.53 (m, 7H), 3.91-3.95 (m,1H), 3.99 (q, J = 7.0 carboxylate Hz, 2H). 2-67 Isomer 2: ethyl 2-55 4-127, 234 n (400 MHz, CD₃OD) δ: 1.31-1.34 (m, 3H), 1.41- I m/z 437 (M +H)⁺ [(2S)-1-{[2-(methylamino) and 235 1.47 (m, 2H), 1.85-2.01 (m, 9H),2.34-2.36 (m, (ES+), at 4.10 min, ethoxylcarbonyl} 5H), 2.77-2.79 (m,6H), 3.32-3.34 (m, 6H), 3.33- UV inactive pyrrolidin-2-yl]piperidin-3.37 (m, 2H), 3.41-3.43 (m, 2H), 3.62-3.73 (m, 1 1-yl}-6- H), 3.86-3.90(m, 2H), 4.12-4.14 (m, 2H). azaspiro[3.4]octane- 6-carboxylate 2-68Isomer 2: ethyl 2-{4-[(2S)- 127 and z (400 MHz, DMSO-d₆) δ: 1.03-1.22(m, 5H), 1.30- I m/z 382 (M + H)⁺ 1-(2- 240 1.41 (m, 1H), 1.42-1.68 (m,8H), 1.69-1.78 (m, (ES+), at 4.71 min, fluoroethyl)pyrrolidin-2- 2H),1.76-1.88 (m, 2H), 1.92-2.01 (m, 2H), 2.09- UV inactiveyl]piperidin-1-yl}-6- 2.20 (m, 1H), 2.24-2.43 (m, 2H), 2.44-2.69 (m,azaspiro[3.4]octane-6- 2H), 2.74-2.85 (m, 2H), 2.88-3.17 (m, 3H), 3.23-carboxylate 3.31 (m, 2H), 3.99 (q, J = 7.0 Hz, 2H), 4.33-4.66 (m, 2H).2-69 Isomer 2: ethyl 2-{4-[(2S)- 127 and aa (400 MHz, CD₃OD) δ: 1.27 (t,J = 7.2 Hz, 3H), I m/z 418 (M + H)⁺ 1-(2,2,2- 237 1.29-1.54 (m, 2H),1.60-1.71 (m, 3H), 1.72-1.85 (ES+), at 5.11 min,trifluoroethyl)pyrrolidin-2- (m, 5H), 1.90-2.01 (m, 4H), 2.09-2.17 (m,2H), UV inactive yl]piperidin-1-yl)-6- 2.42-2.50 (m, 1H), 2.55-2.65 (m,1H), 2.76-2.83 azaspiro[3.4]octane-6- (m, 1H), 2.95-3.05 (m, 3H),3.20-3.31 (m, 3H), carboxylate 3.36-3.39 (m, 2H), 3.39-3.44 (m, 2H),4.11 (q, J = 7.2 Hz, 2H). 2-70 Isomer 1: ethyl 2-{4-[(2)- 127 and ab(400 MHz, CD₃OD) δ: 1.23-1.40 (m, 6H), 1.45- I m/z 432 (M + H)⁺1-(3,3,3- 236 1.54 (m, 1H), 1.62-1.71 (m, 3H), 1.72-1.83 (m, (ES+), at5.54 min, trifluoropropyl)pyrrolidin- 4H), 1.85-1.97 (m, 5H), 2.08-2.21(m, 3H), 2.35- UV inactive 2-yl]piperidin-l-yl}-6- 2.46 (m, 3H),2.73-2.80 (m, 1H), 2.92-3.02 (m, azaspiro[3.4]octane-6- 3H), 3.09-3.15(m, 1H), 3.32-3.44 (m, 4H), 4.13 carboxylate (q, J = 7.0 Hz, 2H). 2-70Isomer 2: ethyl 2-{4-[(2S)- 127 and ab (400 MHz, CD₃OD) δ: 1.27 (t, J =7.2 Hz, 3H), I m/z 432 (M + H)⁺ 1-(3,3,3- 236 1.30-1.39 (m, 3H),1.46-1.55 (m, 1H), 1.61-1.69 (ES+), at 5.39 min,trifluoropropyl)pyrrolidin- (m, 2H), 1.74-1.84 (m, 4H), 1.90-1.99 (m,4H), UV inactive 2-yl]piperidin-1-yl)-6- 2.09-2.23 (m, 3H), 2.31-2.47(m, 4H), 2.73-2.32 azaspiro[3.4]octane-6- (m, 1H), 2.95-3.03 (m, 3H),3.09-3.16 (m, 1H), carboxylate 3.28 (s, 2H), 3.37-3.43 (m, 3H), 4.11 (q,J = 7.2 Hz, 2H). 2-71 Isomer 2: ethyl 2-{4-[(2S)- 127 and w (400 MHz,CD₃OD) δ: 1.21-1.42 (m, 9H), 1.54- I m/z 394 (M + H)⁺ 1-(2- 231 1.99 (m,12H), 2.07-2.18 (m, 2H), 2.26-2.51 (m, (ES+), at 4.55 min,methoxyethyl)pyrrolidin- 2H), 2.76-2.85 (m, 1H), 2.95-3.09 (m, 2H),3.16- UV inactive 2-yl]piperidin-1-yl}-6- 3.44 (m, 7H) 3.52-3.59 (m,2H), 4.11 (q, J = 7.0 azaspiro[3.4]octane-6- Hz, 2H). carboxylate 2-72Isomer 2: ethyl 2-{4-[(2S)- 127 and ac (400 MHz, CD₃OD) δ: 1.22-1.29 (m,4H), 1.30- I m/z 408 (M + H)⁺ 1-(2-methoxy-2- 233 1.38 (m, 2H),1.45-1.54 (m, 2H), 1.64-1.85 (m, (ES+), at 4.56 min,oxoethyl)pyrrolidin-2- 7H), 1.92-2.00 (m, 3H), 2.09-2.17 (m, 2H), 2.40-UV inactive yl]piperidin-1-yl}-6- 2.48 (m, 2H), 2.54-2.59 (m, 2H),2.88-3.04 (m, azaspiro[3.4]octane-6- 3H), 3.18-3.22 (m, 2H), 3.23-3.25(m, 2H), 3.33- carboxylate 3.45 (m, 1H), 3.53-3.60 (m, 2H), 3.39-3.73(m, 1H), 4.08-4.15 (m, 2H). 2-73 Isomer 1: ethyl 2-(4-{(2S)- 127 and ad(400 MHz, CD₃OD) δ: 1.20-1.43 (m, 9H), 1.52- I m/z 421 (M + H)⁺1-[2-(dimethylamino)-2- 238 1.81 (m, 7H), 1.84-1.98 (m, 5H), 2.12-2.22(m, (ES+), at 3.94 min, oxoethyl]pyrrolidin-2- 1H), 2.33-2.41 (m, 1H),2.53-2.57 (m, 1H), 2.84- UV inactive yl)piperidin-1-yl)-6- 2.90 (m, 1H),2.94 (s, 2H), 3.00-3.06 (m, 2H), 3.13 azaspiro[3.4]octane-6- (s, 1H),3.19-3.21 (m, 2H), 3.22-3.27 (m, 1H), carboxylate 3.36-3.42 (m, 4H),3.55-3.63 (m, 1H), 4.13 (d, J = 7.1 Hz, 2H). 2-73 Isomer 2: ethyl2-(4-{(2S)- 127 and ad (400 MHz, CD₃OD) δ: 1.21-1.44 (m, 8H), 1.54- Im/z 421 (M + H)⁺ 1-[2-(dimethylamino)-2- 238 2.03 (m, 12H), 2.10-2.24(m, 2H), 2.31-2.43 (m, (ES+), at 4.08 min, oxoethyl]pyrrolidin-2- 1H),2.53-2.59 (m, 1H), 2.84-2.90 (m, 1H), 2.94 UV inactiveyl}pipendin-1-yl)-6- (s, 2H), 3.02-3.12 (m, 2H), 3.13 (s, 1H), 3.23-3.30azaspire[3.4]octane-6- (m, 3H), 3.36-3.46 (m, 4H), 3.54-3.63 (m, 1H),carboxylate 4.11 (d, J = 7.10 Hz, 2H). 2-74 Isomer 2: ethyl 2-{4-[(2S)-127 and w (400 MHz, DMSO-d₆) δ: 1.07-1.22 (m, 5H), 1.44- I m/z 426 (M +H)⁺ 1-benzylpyrrolidin-2- 232 1.72 (m, 9H), 1.73-1.76 (m, 4H), 1.93-2.07(m, (ES+), at 6.30 min, yl]piperidin-1-yl}-6- 2H), 2.32-2.88 (m, 6H),3.05-3.28 (m, 5H), 3.87- UV active azaspiro[3.4]octane-6- 4.17 (m, 3H),7.18-7.37 (m, 5H). carboxylate 2-75 Isomer 2: ethyl 2-{4-[(2S)- 127 andm (400 MHz, DMSO-d₈) δ: 1.16 (t, J = 7.17, 3H), I m/z 409 (M + H)⁺1-(methylcarbamothioyl) 239 1.22-1.54 (m, 5H), 1.70-1.86 (m, 9H),1.90-2.03 (ES+), at 4.10 min, pyrrolidin-2-yl]piperidin- (m, 3H),2.64-2.75 (m, 6H), 3.11-3.45 (m, 6H), UV inactive 1-yl}-6- 4.00 (q, J =7.0 Hz, 2H) 4.29 (s, 1H), 7.23 (s, 1H). azaspiro[3.4]octane-6-carboxylate 2-76 Isomer 1: ethyl 2-{4-[2- 2, 243 de (400 MHz, DMSO-d₆)δ: 1.13 (t, J = 7.1 Hz, 3H), M m/z 441 (M + H)⁺ (methylcarbamoyl)-2,3-and 244 1.27-1.57 (m, 5H), 1.56-1.76 (m, 4H), 1.83-2.01 (ES+), at 1.97min, dihydro-1H-isoindol-1- (m, 3H), 2.57-2.70 (m, 5H), 2.70-2.81 (m,1H), UV active yl]piperidin-1-yl}-6- 3.10-3.25 (m, 4H), 3.97 (q, J = 7.1Hz, 2H), 4.36- azaspiro[3.4]octane-6- 4.48 (m, 1H), 4.51-4.65 (m, 1H),4.96-5.09 (m, carboxylate 1H), 6.19-6.30 (m, 1H), 7.16-7.37 (m, 4H).2-76 Isomer 2: ethyl 2-{4-[2- 2, 243 ae (400 MHz, DMSO-d₆) δ: 1.12 (t, J= 7.1 Hz, 3H), M m/z 441 (M + H)⁺ (methylcarbamoyl)-2,3- and 2441.28-1.57 (m, 4H), 1.57-1.72 (m, 2H), 1.72-1.83 (ES+), at 1.99 min,dihydro-1H-isoindol-1- (m, 2H), 1.83-2.01 (m, 3H), 2.27-2.34 (m, 1H), UVactive yl]piperidin-1-yl}-6- 2.57-2.69 (m, 6H), 2.71-2.80 (m, 1H),3.01-3.12 azaspiro[3.4]octane-6- (m, 2H), 3.16-3.28 (m, 2H), 3.95 (q, J= 7.1 Hz, carboxylate 2H), 4.38-4.49 (m, 1H), 4.52-4.64 (m, 1H), 4.97-5.10 (m, 1H), 6.20-6.31 (m, 1H), 7.20-7.37 (m, 4H). 2-77 Isomer 2: ethyl2-{4-(2S)- 127 and af (400 MHz, CD₃OD) δ: 1.24 (td, J = 7.0, 1.5 Hz, 3 Im/z 412 (M + H)⁺ 1-phenylpyrrolidin-2- 172 H), 1.32-1.49 (m, 2 H),1.53-1.62 (m, 1 H), 1.63- (ES+), at 6.19 min, yl]piperidin-l-yl)-6- 1.73(m, 2 H), 1.75-1.85 (m, 2 H), 1.85-2.03 (m, 8 UV activeazaspiro[3.4]octane-6- H), 2.04-2.15 (m, 2 H), 2.68-2.81 (m, 1 H), 2.89-carboxylate 3.02 (m, 2 H), 3.06-3.17 (m, 1 H), 3.26 (s, 2 H), 3.33-3.43(m, 2 H), 3.45-3.54 (m, 1 H), 3.68-3.76 (m, 1 H), 4.09 (q, J = 7.0 Hz, 2H), 6.56-6.64 (m, 3 H), 7.08-7.19 (m, 2 H) 2-78 Isomer 2: methyl 2-55 4-157 and ag (400 MHz, CD₃OD) δ: 1.25-2.14 (m, 18 H), 2.66- I m/z 399 (M +H)⁺ [(2S)-1-(pyridin-2- 176 2.79 (m, 1 H), 2.88-3.00 (m, 2 H), 3.25 (d,J = 1.5 (ES+), at 4.56 min, yl)pyrrolidin-2- Hz, 2 H), 3.33-3.45 (m, 2H), 3.47-3.56 (m, 1 H), UV active yl]piperidin-1-yl}-6- 3.66 (s, 3 H),4.01-4.10 (m, 1 H), 6.51-6.58 (m, 2 azaspiro[3.4]octane- H), 7.45-7.53(m, 1 H), 7.97-8.01 (m, 1 H) 6-carboxylate 2-79 Isomer 2: ethyl2-{4-[(2S)- 127 and ag (400 MHz, CDCl₃) δ: 1.19-1.21 (m, 1H), 1.29-1.31I m/z 413 (M + H)⁺ 1-(pyridin-2-yl)pyrrolidin- 176 (m, 6H), 2.05-2.12(m, 4H), 2.13-2.14 (m, 8H), (ES+), at 5.05 min, 2-yl]piperidin-l-yl}-6-2.51-2.53 (m, 1H), 2.97-2.98 (m, 3H), 3.14-3.18 UV activeazaspiro[3.4]octane-6- (m, 2H), 3.24-3.28 (m, 3H), 3.41-3.43 (m, 1H),carboxylate 4.02-4.05 (m, 1H), 4.12-4.15 (m, 2H), 6.40 (d, J = 7.0 Hz,1H), 6.54 (dd, J = 7.0 and 7.0, Hz, 1H), 7.41 (dd, J = 7.0 and 7.0 Hz,1H), 8.17 (d, J = 7.0 Hz, 1H). 2-80 Isomer 1: ethyl 2-{4-[(2S)- 127 andah (400 MHz, CD₃OD) δ: 1.15-2.18 (m, 18 H), 1.25 I m/z 413 (M + H)⁺1-(pyridin-4-yl)pyrrolidin- 175 (t, J = 7.2 Hz, 3 H), 2.69-2.81 (m, 1H), 2.90-3.00 (ES+), at 4.49 min, 2-yl]piperidin-1-yl}-6- (m, 2 H),3.32-3.41 (m, 2 H), 3.46-3.54 (m, 1 H), UV active azaspiro[3.4]octane-6-3.85-3.92 (m, 1 H), 4.05-4.15 (m, 2 H), 6.60 (d, carboxylate J = 6.4 Hz,2 H), 8.04 (d, J = 4.9 Hz, 2 H). 2 protons obscured by MeOH peak. 2-80Isomer 2: ethyl 2-{4-[(2S)- 127 and ah (400 MHz, CD₃OD) δ: 1.13-2.18 (m,21 H), 2.72- I m/z 413 (M + H)⁺ 1-(pyridin-4-yl)pyrrolidin- 175 2.83 (m,1 H), 2.93-3.02 (m, 2 H), 3.26 (s, 2 H), (ES+), at 4.65 min,2-yl]piperidin-1-yl)-6- 3.34-3.43 (m, 2 H), 3.47-3.59 (m, 1 H),3.88-3.96 UV active azasdiro[3.4]octane-6- (m, 1 H), 4.09 (q, J = 7.0Hz, 2 H), 6.64 (d, J = 6.7 carboxylate Hz, 2 H), 8.04 (d, J = 6.4 Hz, 2H). 2-81 Isomer 2: ethyl 2-(4-[(2S)- 127 and ah (400 MHz, CD₃OD) δ:1.21-1.28 (m, 3 H), 1.35- I m/z 414 (M + H)⁺ 1-(pyrimidin-2- 169 1.82(m, 6 H), 1.86-2.14 (m, 10 H), 2.68-2.79 (m, (ES+), at 4.54 min,yl)pyrrolidin-2- 1 H), 2.90-2.99 (m, 2 H), 3.26 (s, 2 H), 3.34-3.43 UVactive yl]piperidin-l-yl}-6- (m, 2 H), 3.46-3.67 (m, 2 H), 4.09 (q, J =7.0 Hz, 2 azaspiro[3.4]octane-6- H), 4.17-4.26 (m, 1 H), 4.56-4.70 (m, 1H), 6.57 (t, carboxylate J = 4.9 Hz, 1 H), 8.29 (d, J = 4.0 Hz, 2 H)2-82 Isomer 2: ethyl 2-{4-[(2S)- 40 and ai (400 MHz, DMSO-d₅) δ: 1.17(t, 3 H), 1.21-1.36 E m/z 419 (M + H)⁺ 1-(1,3-thiazol-2- 127 (m, 4 H),1.39-1.65 (m, 4 H), 1.67-1.82 (m, 4 H), (ES+), at 4.67 min,yl)pyrrolidin-2- 1.83-2.05 (m, 6 H), 2.76-2.86 (m, 2 H), 3.16-3.31 UVactive yl]piperidin-1-yl)-6- (m, 5 H), 3.38-3.45 (m, 1 H), 3.73-3.80 (m,1 H), azaspiro[3.4]octane- 4.00 (q, J = 7.0 Hz, 2 H), 6.70 (d, J = 3.7Hz, 1 H), 6-carboxylate 7.13 (d, J = 3.7 Hz, 1 H) 2-83 Isomer 2: ethyl2-(4-[(2S)- 127 and ai (400 MHz, DMSO-d₅) δ: 1.39-1.41 (m, 4H), 1.42- Im/z 420 (M + H)⁺ 1-(1,3,4-thiadiazol-2- 256 1.43 (m, 3H), 1.60-1.71 (m,3H), 1.80-1.83 (m, (ES+), at 4.08 min, yl)pyrrolidin-2- 3H), 1.97-2.02(m, 9H), 3.11-3.13 (m, 2H), 3.21- UV active yl]piperidin-1-yl}-6- 3.23(m, 4H), 3.31-3.36 (m, 1H), 3.91-3.93 (m, azaspiro[3.4]octane- 1H),4.12-4.13 (q, 2H, J = 6.2 Hz), 8.62 (s, 1H). 6-carboxylate 2-84 Isomer2: ethyl 2-{4- 2 and aj (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), Em/z 394 (M + H)⁺ [(2R)-2- 159 1.42-1.59 (m, 2 H), 1.72-1.97 (m, 11 H),2.02-2.17 (ES+), at 3.29 min, (methoxycarbonyl) (m, 3 H), 2.43 (t, J =10.9 Hz, 1 H), 2.58-2.78 (m, UV inactive pyrrolidin-1-yl]piperidin- 2H), 2.82-2.92 (m, 2 H), 3.01-3.11 (m, 1 H), 3.25 1-yl}-6- (s, 2 H), 3.37(q, J = 6.6 Hz, 2 H), 3.49 (dd, J = azaspiro[3.4]octane-6- 9.4, 3.51 Hz,1 H), 3.38 (s, 3 H), 4.08 (q, J = 7.0 carboxylate Hz, 2 H) 2-85 Isomer2: ethyl 2-{4-[(2S)- 2 and ak (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz,3 H), G m/z 393 (M + H)⁺ 2-(methylcarbamoyl) 139 1.28-1.44 (m, 2 H),1.50-2.03 (m, 11 H), 2.15-2.30 (ES+) at 5.15 min,pyrrolidin-1-yl]piperidin- (m, 1H), 2.33-2.64 (m, 5 H), 2.68-2.81 (m, 2H), UV inactive 1-yl}-6- 2.97-3.19 (m, 4 H), 3.22-3.39 (m, 5 H), 3.99(q, azaspiro[3.4]octane-6- J = 7.0 Hz, 2 H), 7.67 (q, J = 4.6 Hz, 1 H).carboxylate 2-86 Mixture of diasteromers: Example ao (400 MHz, CD₃OD) δ:1.18-1.30 (m, 3 H), 1.75 E m/z 416 ((M + H)⁺ 1-{1-[6-(ethoxycarbonyl)-2-87 (br. s., 2 H), 1.85-2.04 (m, 4 H), 2.06-2.22 (m, 2 (ES+), at 1.62min, 6-azaspiro[3.4]oct-2- H), 2.23-2.42 (m, 3 H), 2.45-2.72 (m, 3 H),2.79- UV inactive yl]piperidin-4-yl}-4,4- 2.91 (m, 1 H), 2.99 (dt, J =17.4, 10.6 Hz, 1 H), difluoro-D-proline 3.17-3.27 (m, 2 H), 3.33-3.55(m, 7 H), 4.03-4.16 (m, 2 H) OH not observed. 2-87 Isomer 2: ethyl2-(4-[(2R)- 2 and aL (400 MHz, DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H), Em/z 430 (M + H)⁺ 4,4-difluoro-2- 260 1.20-1.33 (m, 2 H), 1.62-1.83 (m, 8H), 1.90-1.97 (ES⁺), at 3.64 min, (methoxycarbonyl) (m, 3 H), 2.53-2.62(m, 4 H), 3.11 (d, J = 6.2 Hz, 2 UV inactive pyrrolidin-1-yl]piperidin-H), 3.19-3.26 (m, 5 H), 3.61 (s, 3 H), 3.31-3.85 1-yl}-6- (m, 1 H), 3.97(q, J = 7.0 Hz, 2 H) azaspiro[3.4]octane-6- carboxylate 2-88 Isomer 2:ethyl 2-{4- Example am (400 MHz, DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H),E m/z 420 (M + H)⁺ [(2R)-4,4-difluoro-2- 2-87 and 1.32 (q, J = 12.0 Hz,2 H), 1.49-1.66 (m, 3 H), (ES⁺), at 2.96 min, (methylcarbamoyl) 1681.66-1.75 (m, 3 H), 1.75-1.86 (m, 2 H), 1.94 (dd, UV inactivepyrrolidin-1-yl]piperidin- J = 10.9, 7.4 Hz, 2 H), 2.03-2.22 (m, 1 H),2.33- 1-yl}-6- 2.38 (m, 1 H), 2.52-2.63 (m, 5 H), 2.68-2.79 (m, 2azasoiro[3.4]octane-6- H), 2.91-3.07 (m, 1 H), 3.11 (d, J = 5.9 Hz, 2H), carboxylate 3.18-3.29 (m, 3 H), 3.48 (dd, J = 9.8, 5.5 Hz, 1 H),3.97 (q, J = 7.0 Hz, 2 H), 7.82 (q, J = 4.7 Hz, 1 H) 2-89 Isomer 2:ethyl 2-{4- Example am (400 MHz, DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H),E m/z 443 (M + H)⁺ [(2R)-2- 2-87 and 1.19-1.33 (m, 2 H), 1.51-1.75 (m, 6H), 1.75-1.84 (ES⁺), at 3.03 min, (dimethylcarbamoyl)- 307 (m, 2 H),1.88-1.99 (m, 2H), 2.08-2.22 (m, 1 H), UV inactive4,4-difluoropyrrolidin-1- 2.53-2.62 (m, 3 H), 2.67-2.73 (m, 2 H), 2.77(s, 3 yl]piperidin-1-yl)-5- H), 2.97 (s, 3 H), 3.11 (d, J = 6.2 Hz, 2H), 3.24 (q, azaspiro[3.4]octane-6- J = 6.8 Hz, 2 H), 3.37-3.47 (m, 2H), 3.97 (q, J = carboxylate 7.2 Hz, 2 H), 4.14 (dd, J = 9.0, 4.7 Hz, 1H) 2-90 Isomer 2: ethyl 2-{4- Example an (400 MHz, CD₃OD) δ: 1.24 (t, J= 7.0 Hz, 3 H), E m/z 415 (M + H)⁺ [(2R)-2-carbamoyl-4,4- 2-87 1.44-1.61(m, 2 H), 1.74-1.98 (m, 9 H), 2.04-2.14 (ES+), at 3.20 min,difluoropyrrolidin-1- (m, 2 H), 2.17-2.31 (m, 1 H), 2.51 (t, J = 10.9Hz, UV inactive yl]piperidin-1-yl)-6- 1 H), 2.57-2.80 (m, 2 H), 2.91 (t,J = 9.5 Hz, 2 H), azaspiro[3.4]octane-6- 2.98-3.15 (m, 1 H), 3.25 (s, 3H), 3.34-3.50 (m, 3 carboxylate H), 3.55 (dd, J = 9.5, 5.5 Hz, 1 H),4.08 (q, J = 7.0 Hz, 2 H) 2-91 Isomer 2: ethyl 2-{4- Example an (400MHz, CD₃OD) δ: 1.24 (t, J = 7.2 Hz, 3 H), E m/z 445 (M + H)⁺[(2R)-4,4-difluoro-2- 2-87 and 1.43-1.58 (m, 2 H), 1.75-1.98 (m, 8 H),2.09 (t, J = (ES+), at 2.62 min, (methoxycarbamoyl) 123 9.3 Hz, 2 H),2.20-2.37 (m, 1 H), 2.43-2.53 (m, 1 UV inactivepyrrolidin-1-yl]piperidin- H), 2.54-2.78 (m, 2 H), 2.84-2.98 (m, 2 H),2.96- 1-yl}-6- 3.15 (m, 1 H), 3.25 (s, 2 H), 3.34-3.45 (m, 3 H),azaspiro[3.4]octane-6- 3.61 (dd, J = 9.6, 5.3 Hz, 1 H), 3.68 (s, 3 H),4.08 carboxylate (q, J = 7.2 Hz, 2 H) NH not observed. 2-92 Isomer 2:ethyl 2-(4- Example an (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), Em/z 459 (M + H)⁺ {(2R)-4,4-diflouoro-2- 2-87 and 1.51 (d, J = 10.9 Hz, 2H), 1.72-1.97 (m, 8 H), (ES+), at 3.63 min, [methoxy(methyl) 1242.03-2.13 (m, 2 H), 2.24 (qd, J = 14.3, 3.1 Hz, 1 UV inactivecarbamoyl]pyrrolidin-1- H), 2.56-2.78 (m, 3 H), 2.86 (d, J = 9.4 Hz, 2H), yl}piperidin-1-yl)-6- 3.07-3.21 (m, 4 H), 3.25 (s, 2 H), 3.33-3.51(m, 3 azaspiro[3.4]octane-6- H), 3.73 (s, 3 H), 4.08 (q, J = 7.0 Hz, 2H), 4.20- carboxylate 4.30 (m, 1 H) 2-93 Isomer 2: ethyl 2-{4-[(2S)- 2,167 aL and (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 429(M + H)⁺ 4,4-difluoro-2- and 262 am 1.26-1.38 (m, 2 H), 1.54-1.66 (m,3H) 1.66-1.75 (ES+), at 2.97 min, (methylcarbamoyl) (m, 3 H), 1.75-1.85(m, 2 H), 1.89-1.99 (m, 2 H), UV inactive pyrrolidin-1-yl]piperidin-2.06-2.19 (m, 1 H), 2.33-2.38 (m, 1 H), 2.54-2.61 1-yl}-6- (m, 5 H),2.71-2.78 (m, 2 H), 2.96-3.06 (m, 1 H), azaspiro[3.4]octane-6- 3.11 (d,J = 5.9 Hz, 2 H), 3.21-3.27 (m, 3 H), 3.45- carboxylate 3.51 (m, 1 H),3.97 (q, J = 7.0 Hz, 2 H), 7.74-7.88 (m, 1 H) 2-94 Isomer 2: ethyl2-{4-[(2S)- 2, 262 aL and (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3H), E m/z 442 (M + H)⁺ 2-(dimethylcarbamoyl)- and 307 am 1.20-1.32 (m, 2H), 1.52-1.75 (m, 6 H), 1.75-1.84 (ES⁺), at 3.03 min,4,4-difluoropyrrolidin-1- (m, 2 H), 1.93 (dd, J = 10.5, 8.2 Hz, 2 H),2.08- UV inactive yl]piperidin-1-yl)-6- 2.20 (m, 1 H), 2.52-2.62 (m, 3H), 2.67-2.72 (m, 2 azaspiro[3.4]octane-6- H), 2.77 (s, 3 H), 2.97 (s, 3H), 3.11 (d, J = 6.2 Hz, carboxylate 2 H), 3.21-3.27 (m, 2 H), 3.36-3.44(m, 2 H), 3.93- 4.01 (m, 2 H), 4.14 (dd, J = 9.0, 4.7 Hz, 1 H) 2-95Isomer 2: ethyl 2-{4- 2 and aw (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0Hz, 3 H), E m/z 408 (M + H)⁺ [(2R)-2- 293 1.19 (s, 3 H), 1.27-1.38 (m, 2H), 1.40-1.51 (m, 3 (ES⁺), at 4.06 min, (methoxycarbonyl)-2- H),1.52-1.74 (m, 7 H), 1.75-1.65 (m, 2 H), 1.87- UV inactivemethylpyrrolidin-1- 1.93 (m, 2 H), 1.98-2.08 (m, 1 H), 2.52-2.62 (m, 1yl]piperidin-1-yl}-6- H), 2.67-2.65 (m, 3 H), 2.89 (q, J = 7.5 Hz, 1 H),azaspiro[3.4]octane-6- 3.11 (d, J = 6.6 Hz, 2 H), 3.24 (q, J = 6.8 Hz, 2H), carboxylate 3.55 (s, 3 H), 3.97 (q, J = 7.0 Hz, 2 H) 2-96 Isomer 2:ethyl 2-[4-(6- 2 and aw (400 MHz, DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H),E m/z 406 (M + H)⁺ oxo-7-oxa-1- 300 1.25-1.50 (m, 3H) 1.50-1.68 (m, 4H), 1.68-1.86 (ES⁺), at 5.24 min, azaspiro[4.4]non-1- (m, 8 H),1.86-2.02 (m, 4 H), 2.18-2.35 (m, 1 H), UV inactiveyl)piperidin-1-yl]-6- 2.53-2.67 (m, 1 H), 2.67-2.85 (m, 2 H), 2.95-3.07azaspiro[3.4]octane-6- (m, 1 H), 3.11 (d, J = 6.6 Hz, 2 H), 3.24 (q, J =6.6 carboxylate Hz, 2 H), 3.97 (q, J = 7.0 Hz, 2 H), 4.06-4.18 (m, 1 H),4.32 (t, J = 8.6 Hz, 1 H) 2-97 Isomer 1: ethyl 2-{4-[(4S)- 2 and aw (400MHz, DMSO-d₈) δ: 1.08-1.18 (m, 3 H), 1.32 E m/z 412 (M + H)⁺4-(methoxycarbonyl)-1,3- 286 (quin, J = 11.9 Hz, 2 H), 1.58-1.87 (m, 8H), 1.96 (ES⁺), at 3.62 min, thiazolidin-3-yl]piperidin- (t, J = 9.4 Hz,2 H), 2.32-2.38 (m, 1 H), 2.59 (t, J = UV inactive 1-yl}-6- 7.2 Hz, 1H), 2.72 (d, J = 8.2 Hz, 2 H), 2.93-3.13 azaspiro[3.4]octane-6- (m, 2H), 3.14-3.25 (m, 4 H), 3.60 (s, 3 H), 3.93 carboxylate (d, J = 9.8 Hz,1 H), 3.98 (q, J = 7.0 Hz, 2 H), 4.26 (d, J = 9.4 Hz, 1 H), 4.41 (d, J =5.5 Hz, 1 H) 2-97 Isomer 2: ethyl 2-{4-[(4S)- 2 and aw (400 MHz,DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 412 (M + H)⁺4-(methoxycarbonyl)-1,3- 286 1.24-1.43 (m, 2 H), 1.57-1.86 (m, 8 H),1.88-2.01 (ES⁺), at 3.78 min, thiazolidin-3-yl]piperidin- (m, 2 H),2.33-2.38 (m, 1 H), 2.58 (t, J = 6.8 Hz, 1 UV inactive 1-yl)-6- H), 2.72(d, J = 9.0 Hz, 2 H), 2.93-3.03 (m, 1 H), azaspiro[3.4]octane-6- 3.06(d, J = 2.3 Hz, 1 H), 3.08-3.17 (m, 2 H), 3.24 carboxylate (q, J = 6.8Hz, 2 H), 3.60 (s, 3 H), 3.88-4.04 (m, 3 H), 4.26 (d, J = 9.4 Hz, 1 H),4.41 (d, J = 5.9 Hz, 1 H) 2-98 Isomer 2: ethyl 2-{4- 151 and ap (400MHz, DMSO-d₅) δ: 1.13 (t, J = 7.2 Hz, 3 H), E m/z 354 (M + H)⁺[(3R)-3-fluoropyrrolidin- 262 1.26-1.35 (m, 2 H), 1.59-1.36 (m, 10 H),1.88-1.99 (ES⁺), at 3.06 min, 1-yl]piperidin-1-yl}-6- (m, 6 H),2.71-2.88 (m, 3 H), 3.12 (d, J = 7.0 Hz, 2 UV inactiveazaspiro[3.4]octane-6- H), 3.20-3.29 (m, 3 H), 3.97 (q, J = 7.0 Hz, 2H), carboxylate 5.02-5.13 (m, 1 H) 2-99 Isomer 2: ethyl 2-{4-[(3S)- 151and ap (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 354 (M +H)⁺ 3-fluoropyrrolidin-1- 263 1.25-1.37 (m, 2 H), 1.54-1.34 (m, 10 H),1.85-1.99 (ES⁺), at 3.03 min, yl]piperidin-l-yl)-6- (m, 6 H), 2.71-2.85(m, 3 H), 3.12 (d, J = 7.0 Hz, 2 UV inactive azaspiro[3.4]octane-6- H),3.20-3.26 (m, 3 H), 3.97 (q, J = 7.0 Hz, 2 H), carboxylate 5.03-5.15 (m,1 H) 2- Isomer 2: ethyl 2-[4-(3,3- 88 and ap (400 MHz, DMSO-d₆) δ: 1.13(t, J = 7.0 Hz, 3 H), E m/z 372 (M + H)⁺ 100 difluoropyrrolidin-1- 1511.24-1.31 (m, 2 H), 1.57-1.37 (m, 7 H), 1.89-2.06 (ES⁺), at 3.38 min,yl)piperidin-1-yl]-6- (m, 3 H), 2.11-2.27 (m, 1 H), 2.44 (br. s., 1 H),UV inactive azaspiro[3.4]octane-6- 2.55-2.61 (m, 4 H), 2.68-2.71 (m, 2H), 2.87 (t, J = carboxylate 14.1 Hz, 2 H), 3.12 (d, J = 7.0 Hz, 2 H),3.20-3.27 (m, 2 H), 3.97 (q, J = 7.0 Hz, 2 H) 2- Isomer 2: ethyl2-{4-[(2S)- 2 and aw (400 MHz, DMSO-d6) δ: 1.13 (t, J = 7.0 Hz, 3 H), Em/z 404 (M + H)⁺ 101 2-(trifluoromethyl) 278 1.29-1.47 (m, 2 H),1.55-1.85 (m, 12 H), 1.89-2.00 (ES⁺), at 4.22 min,pyrrolidin-1-yl]piperidin- (m, 2 H), 2.54-2.68 (m, 2 H), 2.70-2.60 (m, 3H), UV inactive 1-yl]-6- 3.11 (d, J = 5.9 Hz, 2 H), 3.19-3.27 (m, 3 H),3.49- azaspiro[3.4]octane-6- 3.61 (m, 1 H), 3.96 (q, J = 7.0 Hz, 2 H)carboxylate 2- Isomer 2: ethyl 2-{4- 2 and aw (400 MHz, DMSO-d₆) δ:1.10-1.16 (m, 3 H), 1.21 E m/z 368 (M + H)⁺ 102 [(2R)-2- 296 (s, 2 H),1.27-1.50 (m, 3 H), 1.50-1.56 (m, 2 H), (ES⁺), at 5.04 min,(fluoromethyl)pyrrolidin- 1.56-1.72 (m, 3 H), 1.72-1.92 (m, 5 H),1.92-2.03 UV inactive 1-yl]piperidin-1-yl}-6- (m, 2 H), 2.09-2.21 (m, 1H), 2.23-2.45 (m, 4 H), azaspire[3.4]octane-6- 2.69-2.94 (m, 1 H),3.09-3.21 (m, 2 H), 3.21-3.29 carboxylate (m, 4 H), 3.98 (q, J = 7.0 Hz,2 H) 2- Isomer 2: ethyl 2-{4- 2 and aw (400 MHz, DMSO-d₅) δ: 1.14 (t, J= 7.0 Hz, 3 H), E m/z 386 (M + H)⁺ 103 [(2R)-2-(difluoromethyl) 2981.18-1.28 (m, 2 H), 1.32-1.49 (m, 2 H), 1.57-1.87 (ES⁺), at 5.62 min,pyrrolidin-1-yl]piperidin- (m, 11 H), 1.89 (s, 1 H), 1.92-2.09 (m, 2 H),2.10- UV inactive 1-yl}-6- 2.23 (m, 1 H), 2.67-2.94 (m, 3 H), 3.06-3.21(m, 3 azaspiro[3.4]octane- H), 3.21-3.26 (m, 2 H), 3.98 (q, J = 7.2 Hz,2 H), 6-carboxylate 5.63-5.78 (m, 1 H) 2- Isomer 2: ethyl 2-{4- 2 and aw(300 MHz, DMSO-d₅) δ: 1.16 (t, J = 7.0 Hz, 3 H), E m/z 404 (M + H)⁺ 104[(2R)-2-(trifluoromethyl) 274 1.31-1.54 (m, 2 H), 1.54-1.91 (m, 12 H),1.97 (t, (ES⁺), at 4.22 min, pyrrolidin-1-yl]piperidin- J = 9.2 Hz, 2H), 2.58-2.75 (m, 2 H), 2.75-2.92 (m, UV inactive 1-yl}-6- 3 H), 3.14(br. s., 2 H), 3.20-3.25 (m, 3 H) 3.45- azaspiro[3.4]octane-6- 3.66 (m,1 H), 3.99 (q, J = 7.1 Hz, 2 H) carboxylate 2- Isomer 2: ethyl 2-[4-(3-2 and aw (400 MHz, DMSO-d₆) δ: 0.27 (br. s., 1 H), 0.45- E m/z 348 (M +H)⁺ 105 azabicyclo[3.1.0]hex-3- 280 0.54 (m, 1 H), 1.13 (t, J = 7.0 Hz,3 H), 1.22-1.40 (ES⁺), at 3.78 min, yl)piperidin-1-yl]-6- (m, 4 H),1.57-1.86 (m, 8 H), 1.94 (t, J = 8.2 Hz, 2 UV inactiveazaspiro[3.4]octane-6- H), 1.98-2.14 (m, 1 H), 2.19-2.36 (m, 2 H), 2.59-carboxylate 2.73 (m, 3 H), 2.93 (d, J = 8.2 Hz, 2 H), 3.11 (d, J = 5.5Hz, 2 H), 3.20-3.25 (m, 2 H), 3.96 (q, J = 7.2 Hz, 2 H) 2- Isomer 2:ethyl 2-{4-[(2S)- 2 and aj (400 MHz, CD₃OD) δ: 1.11 (d, J = 5.9 Hz, 3H), E m/z 386 (M + H)⁺ 106 4,4-difluoro-2- 125 1.19-1.35 (m, 4 H),1.41-1.63 (m, 2 H), 1.71-1.97 (ES+), at 3.98 min, methylpyrrolidin-1-(m, 9 H), 2.05-2.15 (m, 2 H), 2.31-2.46 (m, 1 H), UV inactiveyl]piperidin-1-yl}-6- 2.63-2.82 (m, 2 H), 2.89-3.00 (m, 2 H), 3.08-3.22azaspiro[3.4]octane-6- (m, 2 H), 3.25 (s, 2 H), 3.34-3.42 (m, 2 H), 4.09carboxylate (q, J = 7.0 Hz, 2 H) 2- Isomer 2: ethyl 2-{4- 2 and aj (400MHz, CD₃OD) δ: 1.18-1.29 (m, 3 H), 1.43- E m/z 402 (M + H)⁺ 107[(2R)-4,4-difluoro-2- 126 1.60 (m, 2 H), 1.74-1.97 (m, 8 H), 2.04-2.23(m, 3 (ES+), at 3.23 min, (hydroxymethyl)pyrolidin- H), 2.24-2.41 (m, 1H), 2.66-2.81 (m, 2 H), 2.88- UV inactive 1-yl]piperidin-1-yl}-6- 3.11(m, 3 H), 3.14-3.28 (m, 5 H), 3.38 (q, J = 6.4 azaspiro[3.4]octane-6-Hz, 2 H), 3.44-3.59 (m, 2 H), 4.09 (q, J = 7.2 Hz, 2 carboxylate H) 2-Isomer 2: ethyl 2-{4- 2 and as (400 MHz, CDCl₃) δ: 1.25 (t, J = 7.0 Hz,3 H), B m/z 416 (M + H)⁺ 108 [(2R)-4,4-difluoro-2- 174 1.41-1.99 (m, 10H), 2.01-2.24 (m, 3 H), 2.24-2.44 (ES+), at 4.04 min, (methoxymethyl)(m, 1 H), 2.57-2.78 (m, 1 H), 2.83-3.11 (m, 3 H), UV inactivepyrrolidin-1-yl]piperidin- 3.14-3.47 (m, 9 H), 3.35 (s, 3H), 4.11 (q, J= 7.2 1-yl}-6- Hz, 2 H) azaspiro[3.4]octane-6- carboxylate 2- Isomer 2:ethyl 2-{4- 2 and as (400 MHz., CDCl₃) δ: 1.14 (d, J = 6.2 Hz, 3 H), Bm/z 416 (M + H)⁺ 109 [(2R)-4,4-difluoro-2-(1- 179 1.24 (t, J = 7.0 Hz, 3H), 1.40-2.20 (m, 13 H), (ES+), at 4.20 min, hydroxyethyl)pyrrolidin-1-2.25-2.43 (m, 1 H), 2.58-2.83 (m, 2 H), 2.83-3.10 UV inactiveyl]piperidin-1-yl}-6- (m, 4 H), 3.10-3.34 (m, 4 H), 3.34-3.44 (m, 2 H),azaspiro[3.4]octane-6- 3.49-3.57 (m, 1 H), 4.11 (q, J = 7.0 Hz, 2 H)carboxylate 2- Isomer 4: ethyl 2-{4- 2 and as (400 MHz, CDCl₃) δ: 1.08(d, J = 6.6 Hz, 3 H), B m/z 416 (M + H)⁺ 109 [(2R)-4,4-difluoro-2-(1-179 1.24 (t, J = 6.6 Hz, 3 H), 1.47-2.19 (m, 13 H), (ES+), at 3.99 min,hydroxyethyl)pyrrolidin-1- 2.20-2.37 (m, 1 H), 2.60-2.72 (m, 2 H),2.89-3.02 UV inactive yl]piperidin-1-yl}-6- (m, 4 H), 3.02-3.17 (m, 2H), 3.18-3.44 (m, 4 H), azaspiro[3.4]octane-6- 3.85-3.94 (m, 1 H), 4.11(q, J = 6.8 Hz, 2 H) carboxylate 2- Mixture of 2 and ax (400 MHz,DMSO-d₅) δ: 0.85-1.08 (m, 5H), 1.09- N m/z 430 (M + H)⁺ 110diasteremomers: ethyl 2- 258 1.21 (m, 4H), 1.21-1.44 (m, 2H), 1.44-1.88(m, (ES+), at 2.14 + {4-[(2R)-4,4-difluoro-2- 6H), 1.88-2.35 (m, 4H),2.55-3.17 (m, 6H), 3.17- 2.16 min, UV (2-hydroxypropan-2- 3.39 (m, 3H),3.42-3.76 (m, 3H), 3.94 -4.09 (m, inactive yl)pyrrolidin-1- 3H), 4.23(s, 1H). yl]piperidin-1-yl}-6- azaspiro[3.4]octane- 6-carboxylate 2-Isomer 2: ethyl 2-[4-(2- 2 and ap ¹H NMR (400 MHz, DMSO-d₆) δ: 1.14 (t,J = 7.2 E m/z 350 (M + H)⁺ 111 oxopyrrolidin-1- 269 Hz, 3 H), 1.46 (d, J= 10.2 Hz, 2 H), 1.52-1.66 (m, (ES⁺), at 2.33 min, yl)piperidin-1-yl]-6-2 H), 1.66-1.77 (m, 4 H), 1.77-1.91 (m, 5 H), 1.96 UV inactiveazaspiro[3.4]octane- (t, J = 9.0 Hz, 2 H), 2.14-2.21 (m, 2 H), 2.80 (d,6-carboxylate J = 10.2 Hz, 2 H), 3.12 (d, J = 5.5 Hz, 2 H), 3.22- 3.28(m, 4 H), 3.60-3.74 (m, 1 H), 3.97 (q, J = 7.0 Hz, 2 H) 2- Isomer 2:ethyl 2-[4-(2,5- 2 and as (400 MHz, CDCl₃) δ: 1.25 (t, J = 7.0 Hz, 3 H),B m/z 364 (M + H)⁺ 112 dioxopyrrolidin-1- 193 1.47-1.63 (m, 2 H),1.76-2.11 (m, 8 H), 2.41-2.56 (ES+), at 3.70 min, yl)piperirlin-1-yl]-6-(m, 2 H), 2.58-2.78 (m, 1H), 2.67 (s, 4 H), 2.90- UV activeazaspiro[3.4]octane-6- 3.03 (m, 2 H), 3.19-3.48 (m, 4 H), 3.92-4.06 (m,1 carboxylate H), 4.11 (q, J = 6.9 Hz, 2 H) 2- Isomer 2: ethyl 2-{4- 2and as (400 MHz, CDCl₃) δ: 1.21-1.30 (m, 6 H), 1.57- B m/z 364 (M + H)⁺113 [(2R)-2-methyl-5- 199 1.72 (m, 2 H), 1.74-1.95 (m, 9 H), 1.96-2.07(m, 2 (ES+), at 3.53 min, oxopyrrolidin-1- H), 2.10-2.20 (m, 1 H),2.21-2.33 (m, 1 H), 2.44- UV active yl]piperidin-1-yl}-6- 2.54 (m, 1 H),2.59-2.76 (m, 1 H), 2.32-3.01 (m, 2 azaspiro[3.4]octane-6- H), 3.27 (d,J = 19.9 Hz. 2 H), 3.32-3.45 (m, 2 H), carboxylate 3.75-3.95 (m, 2 H),4.10 (q, J = 6.6 Hz, 2 H) 2- Isomer 2: ethyl 2-{4- 2 and as (400 MHz,CDCl₃) δ: 0.86 (t, J = 7.2 Hz, 3 H), B m/z 376 (M + H)⁺ 114[(2R)-2-ethyl-5- 200 1.22 ad, J = 7.0, 3.1 Hz, 3 H), 1.40-1.53 (m, 1 H),(ES+), at 3.73 min, oxopyrrolidin-1- 1.61 (d, J = 12.1 Hz, 1 H),1.68-1.92 (m, 11 H), UV active yl]piperidin-1-yl)-6- 2.03 (d, J = 8.2Hz, 3 H), 2.18-2.30 (m, 1 H), 2.37- azaspiro[3.4]octane-6- 2.48 (m, 1H), 2.58-2.71 (m, 1 H), 2.82-2.97 (m, 2 carboxylate H), 3.18-3.29 (m, 2H), 3.30-3.42 (m, 2 H), 3.60 (t, J = 8.4 Hz, 1 H), 3.76-3.92 (m, 1 H),4.08 (q, J = 6.9 Hz, 2 H) 2- Isomer 2: ethyl 2-{4-[(2S)- 2 and as (400MHz, CDCl₃) δ: 1.20-1.30 (m, 6 H), 1.54- B m/z 364 (M + H)⁺ 1152-methyl-5-oxopyrrolidin- 202 1.67 (m, 2 H), 1.72-1.96 (m, 9 H),1.98-2.09 (m, 2 (ES+), at 3.53 min, 1-yl]piperidin-1-yl}-6- H),2.09-2.20 (m, 1 H), 2.20-2.32 (m, 1 H), 2.43- UV activeazaspiro[3.4]octane-6- 2.54 (m, 1 H), 2.59-2.74 (m, 1 H), 2.82-3.01 (m,2 carboxylate H), 3.26 (d, J = 19.9 Hz, 2 H), 3.31-3.44 (m, 2 H),3.75-3.95 (m, 2 H), 4.10 (q, J = 6.8 Hz, 2 H 2- Isomer 2: ethyl2-{4-[(2S)- 2 and as (400 MHz, CDCl₃) δ: 0.86 (t, J = 7.2 Hz, 3 H), Bm/z 378 (M + H)⁺ 116 2-ethyl-5-oxopyrrolidin-1- 203 1.22 (td, J = 7.0,3.5 Hz, 3 H), 1.40-1.51 (m, 1 H), (ES+), at 3.73 min,yl]piperidin-1-yl}-6- 1.61 (d, J = 11.7 Hz, 1 H), 1.67-1.91 (m, 11 H),UV active azaspiro[3.4]octane-6- 1.91-2.11 (m, 3 H), 2.19-2.29 (m, 1 H),2.38-2.48 carboxylate (m, 1 H), 2.59-2.63 (m, 1 H), 2.83-2.94 (m, 2 H),3.18-3.29 (m, 2 H), 3.31-3.42 (m, 2 H), 3.60 (t, J = 8.2 Hz, 1 H),3.78-3.89 (m, 1 H), 4.03 (q, J = 7.0 Hz, 2 H) 2- Isomer 2: ethyl2-[4-(2,2- 2 and as (400 MHz, CDCl₃) δ: 1.18-1.32 (m, 9 H), 1.42- B m/z378 (M + H)⁺ 117 dimethyl-5-oxopyrrolidin- 186 1.57 (m, 2 H), 1.63-2.11(m, 10 H), 2.29-2.39 (m, (ES+), at 5.41 min, 1-yl)piperidin-1-yl]-6- 2H), 2.50-2.82 (m, 3 H), 2.86-3.14 (m, 3 H), 3.21- UV activeazaspiro[3.4]octane-6- 3.32 (m, 2 H), 3.32-3.46 (m, 2 H), 4.11 (q, J =6.9 carboxylate Hz, 2 H) 2- Isomer 2: ethyl 2-{4- 2 and as (400 MHz,CDCl₃) δ: 1.17-1.23 (m, 3 H), 1.30 (d, B m/z 366 (M + H)⁺ 118[(4R)-4-methyl-2-oxo-1,3- 205 J = 6.2 Hz, 3 H), 1.66-1.88 (m, 10 H),1.95-2.06 (ES+), at 3.30 min, oxazolidin-3-yl]piperidin- (m, 2 H),2.58-2.68 (m, 1 H), 2.82-2.95 (m, 2 H), UV active 1-yl}-6- 3.17-3.27 (m,2 H), 3.28-3.39 (m, 2 H), 3.53-3.67 azaspiro[3.4]octane-6- (m, 1 H),3.79 (dd, J = 8.2, 5.1 Hz, 1 H), 3.86-3.94 carboxylate (m, 1 H), 4.08(q, J = 7.0 Hz, 2 H), 4.30 (l, J = 8.2 Hz, 1 H) 2- Isomer 2: ethyl 2-{4-2 and as (400 MHz, CDCl₃) δ: 0.85 (t, J = 7.4 Hz, 3 H), B m/z 380 (M +H)⁺ 119 [(4R)-4-ethyl-2-oxo-1,3- 207 1.21 (td, J = 6.9, 3.3 Hz, 3 H),1.52-1.65 (m, 1 H), (ES+), at 3.73 min, oxazolidin-3-yl]piperidin-1.07-1.90 (m, 11 H), 1.98-2.07 (m, 2 H), 2.58-2.68 UV active 1-yl}-6-(m, 1 H), 2.89 (dd, J = 18.9, 9.2 Hz, 2 H), 3.18- azaspiro[3.4]octane-6-3.28 (m, 2 H), 3.35 (dt, J = 19.6, 6.8 Hz, 2 H), carboxylate 3.55-3.66(m, 1 H), 3.77 (dt, J = 7.6, 4.0 Hz, 1 H), 3.95 (dd, J = 8.6, 4.7 Hz, 1H), 4.04-4.11 (m, 2 H), 4.26 (t, J = 8.4 Hz, 1 H) 2- Isomer 2: ethyl2-{4- 2 and as (300 MHz, CDCl₃) δ: 0.89 (dd, J = 10.1, 6.9 Hz, 6 B m/z394 (M + H)⁺ 120 [(4R)-2-oxo-4-(propan-2- 197 H), 1.25 (t, J = 7.1 Hz, 3H), 1.51-2.25 (m, 13 H), (ES+), at 3.93 min, yl)-1,3-oxazolidin-3-2.60-2.78 (m, 1 H), 2.85-3.05 (m, 2 H), 3.21-3.49 UV activeyl]piperidin-1-yl}-6- (m, 4 H), 3.54-3.74 (m, 1 H), 3.74-3.83 (m, 1 H),azaspiro[3.4]octane-6- 4.05-4.21 (m, 4 H) carboxylate 2- Isomer 2: ethyl2-{4-[(4S)- 2 and as (400 MHz, CDCl₃) δ: 1.18-1.25 (m, 3 H), 1.32 (d, Bm/z 366 (M + H)⁺ 121 4-methyl-2-oxo-1,3- 209 J = 5.9 Hz, 3 H), 1.65-1.93(m, 10 H), 1.97-2.09 (ES+), at 3.43 min, oxazolidin-3-yl]piperidin- (m,2 H), 2.58-2.71 (m, 1 H), 2.82-2.96 (m, 2 H), UV active 1-yl}-6-3.18-3.29 (m, 2 H), 3.36 (dt, J = 19.7, 6.7 Hz, 2 azaspiro[3.4]octane-6-H), 3.55-3.69 (m, 1 H), 3.80 (dd, J = 8.2, 5.5 Hz, 1 carboxylate H),3.86-3.97 (m, 1 H), 4.08 (q, J = 6.9 Hz, 2 H), 4.32 (t, J = 8.2 Hz, 1 H)2- Isomer 2: ethyl 2-{4-[(4S)- 2 and as (300 MHz, CDCl₃) δ: 0.90 (t, J =7.5 Hz, 3 H), B m/z 380 (M + H)⁺ 122 4-ethyl-2-oxo-1,3- 211 1.25 (t, J =7.1 Hz, 3 H), 1.52-2.20 (m, 14 H), (ES+), at 3.72 min,oxazolidin-3-yl]pioeridin- 2.62-2.78 (m, 1 H), 2.64-3.06 (m, 2 H),3.22-3.55 UV active 1-yl}-6- (m, 4 H), 3.58-3.72 (m, 1 H), 3.72-3.83 (m,1 H), azaspiro[3.4]octane-6- 3.99 (dd, J = 8.6, 4.7 Hz, 1 H), 4.05-4.19(m, 2 H), carboxylate 4.29 (t, J = 8.6 Hz, 1 H) 2- Isomer 2: ethyl2-{4-[(4S)- 2 and as (400 MHz, CDCl₃) δ: 0.82-0.96 (m, 6 H), 1.25 (s, Bm/z 394 (M + H)⁺ 123 2-oxo-4-(propan-2-yl)-1,3- 188 3 H), 1.56-2.24 (m,13 H), 2.61-2.78 (m, 1 H), (ES+), at 5.16 min,oxazolidin-3-yl]piperidin- 2.85-3.03 (m, 2 H), 3.21-3.48 (m, 4 H),3.55-3.74 UV active 1-yl}-6- (m, 1 H), 3.74-3.83 (m, 1 H), 4.05-4.20 (m,4 H) azaspiro[3.4]octane-6- carboxylate 2- Isomer 2: ethyl 2-[4-(2- 151and aq (400 MHz, CDCl₃) δ: 1.16-1.36 (m, 3 H), 1.45- B m/z 351 (M + H)⁺124 oxoimidazolidin-1- 152 2.23 (m, 13 H), 2.56-2.60 (m, 1 H), 2.83-3.08(m, (ES⁺), at 2.12 min, yl)piperidin-1-yl]-6- 2 H), 3.17-3.52 (m, 7 H),3.63-3.90 (m, 1 H), 4.10 UV inactive azaspiro[3.4]octane-6- (q, J = 7.0Hz, 2 H), 4.24-4.42 (m, 1 H). carboxylate 2- Isomer 2: ethyl 2-[4-(3- 2and ac (300 MHz, CDCl₃) δ: 1.20-1.30 (m, 3 H), 1.61- B m/z 365 (M + H)⁺125 methyl-2-oxoimidazolidin- 213 1.98 (m, 10 H), 2.00-2.15 (m, 2 H),2.62-2.73 (m, (ES+), at 3.07 min, 1-yl)piperidin-1-yl]-6- 1 H), 2.77 (s,3 H), 2.86-2.98 (m, 2 H), 3.21-3.48 UV active azaspiro[3.4]octane-6- (m,5 H), 3.26 (s, 3 H), 3.69-3.85 (m, 1 H), 4.05- carboxylate 4.19 (m, 2 H)2- Isomer 2: ethyl 2-{4-[2- 2 and as (400 MHz, CDCl₃) δ: 1.24 (t, J =7.0 Hz, 3 H), B m/z 402 (M + H)⁺ 126 (1H-pyrazol-5- 181 1.48-2.28 (m, 16H), 2.38 -2.73 (m, 4 H), 2.76- (ES+), at 3.62 min, yl)pyrrolidin-1- 3.02(m, 2 H), 3.07-3.22 (m, 1 H), 3.22-3.43 (m, 4 UV activeyl]piperidin-1-yl}-6- H), 4.10 (q, J = 7.0 Hz, 2 H), 6.15 (br. s., 1 H),azaspiro[3.4]octane-6- 7.52 (d, J = 2.0 Hz, 1 H). One exchangeablecarboxylate proton not observed. 2- Isomer 2: ethyl 2-{4-[2- 2 and ak(400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.2 Hz, 3 H), I m/z 403 (M + H)⁺ 127(1,2-oxazol-3- 318 1.33 (dd, J = 12.1, 11.4 Hz, 2 H), 1.49-1.68 (m, 2(ES⁺), at 4.20 min, yl)pyrrolidin-1- H), 1.68-1.89 (m, 9 H), 1.90-2.02(m, 2 H), 2.03- UV active yl]piperidin-1-yl}-6- 2.17 (m, 1 H), 2.25 (t,J = 11.6 Hz, 1 H), 2.55-2.83 azasoiro[3.4]octane-6- (m, 4 H), 2.83-3.01(m, 1 H), 3.06-3.19 (m, 2 H), carboxylate 3.26 (q, J = 7.0 Hz, 2 H),3.99 (q, J = 7.0 Hz, 2 H), 4.11-4.24 (m, 1 H), 6.22-6.35 (m, 1 H),8.39-8.48 (m, 1 H) 2- Isomer 2: ethyl 2-{4-[2- 2 and aw (400 MHz,DMSO-d₃) δ: 1.13 (t, J = 7.2 Hz, 3 H), E m/z 404 (M + H)⁺ 128(1H-tetrazol-5- 288 1.25-1.50 (m, 2 H), 1.55-1.67 (m, 2 H), 1.67-1.84(ES⁺), at 1.78 min, yl)pyrrolidin-1- (m, 5 H), 1.86-2.05 (m, 6 H),2.15-2.26 (m, 1 H), UV inactive yl]piperidin-1-yl}-6- 2.62 (br. s., 1H), 2.68-2.83 (m, 2 H), 2.94-3.05 azaspiro[3.4]octane-6- (m, 1 H), 3.11(d, J = 5.9 Hz, 2 H), 3.14-3.19 (m, 2 carboxylate H), 3.21-3.27 (m, 3H), 3.95 (q, J = 7.0 Hz, 2 H), 4.62 (br. s., 1 H) 2- Isomer 2: ethyl2-{4-[2-(2- 2 and aw (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), Em/z 418 (M + H)⁺ 129 methyl-2H-tetrazol-5- 308 1.19-1.33 (m, 2 H), 1.44(d, J = 12.1 Hz, 1 H), (ES⁺), at 3.72 min, yl)pyrrolidin-1- 1.49-1.60(m, 2 H), 1.63-1.72 (m, 3 H), 1.73-1.94 UV inactiveyl]piperidin-1-yl}-6- (m, 7 H), 2.11-2.28 (m, 2 H), 2.51-2.64 (m, 3 H),azaspiro[3.4]octane- 2.68 (d, J = 10.2 Hz, 1 H), 3.05-3.16 (m, 3 H),3.23 6-carboxylate (q, J = 6.6 Hz, 2 H), 3.96 (q, J = 7.0 Hz, 2 H), 4.10(s, 3 H), 4.35 (dd, J = 9.2, 5.3 Hz, 1 H) 2- Isomer 1: ethyl 2-{4-[2-(12 and aw (400 MHz, DMSO-d₆) δ: 0.43 (t, J = 6.4 Hz, 3 H), E m/z 418 (M +H)⁺ 130 methyl-1H-tetrazol-5- 308 0.60-0.82 (m, 2 H), 0.91-1.21 (m, 11H), 1.24-1.31 (ES⁺), at 3.61 min, yl)pyrrolidin-1- (m, 3 H), 1.38-1.50(m, 2 H), 1.79-1.95 (m, 2 H), UV inactive yl]piperidin-1-yl}-6-1.95-2.13 (m, 5 H), 2.13-2.24 (m, 1 H), 3.28 (q, azaspiro[3.4]octane- J= 7.2 Hz, 2 H), 3.52 (s, 3 H) , 3.57 (dd, J = 8.2, 6-carboxylate 3.9 Hz,1 H) 2- Isomer 2: ethyl 2-{4-[2-(1- 2 and aw (400 MHz, DMSO-d₅) δ: 0.43(t, J = 7.0 Hz, 3 H), E m/z 418 (M + H)⁺ 130 methyl-1H-tetrazo-5- 3080.66-0.83 (m, 2 H), 0.93-1.00 (m, 2 H), 1.02-1.31 (ES⁺), at 3.80 min,yl)pyrrolidin-1- (m, 12 H), 1.38-1.54 (m, 2 H), 1.83-2.13 (m, 7 H), UVinactive yl]piperidin-1-yl}-6- 2.13-2.24 (m, 1 H), 3.27 (q, J = 7.0 Hz,2 H), 3.52 azaspiro[3.4]octane- (s, 3 H), 3.55-3.51 (m, 1 H)6-carboxylate 2- Isomer 2: ethyl 2-{4- 2 and ak (400 MHz, CD₃OD) δ:1.21-1.30 (m, 3 H), 1.51- I m/z 418 (M + H)⁺ 131 [(2R)-2-(thiophen-2-316 1.66 (m, 2 H), 1.69-1.81 (m, 3 H), 1.81-2.03 (m, 7 (ES⁺), at 5.32min, yl)pyrrolidin-1- H), 2.04-2.16 (m, 2 H), 2.16-2.30 (m, 1 H), 2.41-UV active yl]piperidin-1-yl}-6- 2.55 (m, 1 H), 2.64-2.75 (m, 2 H),2.82-2.99 (m, 2 azaspiro[3.4]octane-6- H), 3.08 (t, J = 10.1 Hz, 1 H),3.36-3.43 (m, 3 H), carboxylate 4.10 (q, J = 7.0 Hz, 2 H), 4.16-4.29 (m,1 H), 4.66 (br. s., 2 H), 6.90-6.97 (m, 2 H), 7.21-7.33 (m, 1 H) 2-Isomer 2: ethyl 2-{4- 2 and ak (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.2Hz, 3 H), I m/z 419 (M + H)⁺ 132 [(2R)-2-(1,3-thiazol-2- 314 1.28-1.48(m, 2 H), 1.51-1.65 (m, 3 H), 1.65-1.88 (ES⁺), at 4.60 min,yl)pyrrolidin-1- (m, 7 H), 1.88-2.03 (m, 2 H), 2.08-2.25 (m, 1 H) UVactive yl]piperidin-1-yl}-6- 2.36-2.47 (m, 1 H), 2.55-2.63 (m, 3 H),2.65-2.86 azaspiro[3.4]octane- (m, 2 H), 3.01-3.20 (m, 3 H), 3.20-3.30(m, 2 H), 6-carboxylate 3.99 (q, J = 7.0 Hz, 2 H), 4.16-4.31 (m, 1 H),7.50 (d, J = 3.4 Hz, 1 H), 7.67 (d, J = 3.1 Hz, 1 H) 2- Isomer 1: ethyl2-{4-[(2S)- 127 and q (400 MHz, CD₃OD) δ: 0.36-0.66 (m, 7H), 0.76- E m/z482 (M + H)⁺ 133 1-(5,7-dihydro-6H- 321 1.38 (m, 15H), 1.87-2.02 (m,1H), 2.09-2.23 (m, (ES+), at 3.90 min, pyrrolo[3,4-b]pyridin-6- 2H),2.62-2.81 (m, 2H), 3.22-3.43 (m, 3H), 3.68- UV activeylcarbonyl)pyrrolidin-2- 3.96 (m, 3H), 3.96-4.34 (m, 3H), 6.48-6.61 (m,yl]piperidin-1-yl}-6- 1H), 7.01 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 4.9Hz, azasoiro[3.4]octane-6- 1H). carboxylate 2- Isomer 2: ethyl2-{4-[(2S)- 127 and q (400 MHz, CD₃OD) δ: 1.13-1.49 (m, 7H), 1.55- E m/z482 (M + H)⁺ 133 1-(5,7-dihydro-6H- 321 2.24 (m, 14H), 2.67-2.83 (m,1H), 2.88-3.04 (m, (ES+), at 4.04 min, pyrrolo[3,4-b]pyridin-6- 2H),3.21-3.77 (m, 3H), 4.02-4.24 (m, 3H), 4.45- UV activeylcarbonyl)pyrrolidin-2- 5.15 (m, 6H), 7.37 (dd, J = 7.7, 5.0 Hz, 1H),7.82 yl]piperidin-1-yl}-6- (d, J = 7.8 Hz, 1H), 8.45 (d, J = 3.4 Hz,1H). azaspiro[3.4]octane-6- carboxylate 2- Isomer 2: ethyl 2-ο4- 2 andaw (300 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.1 Hz, 3 H), E m/z 412 (M + H)⁺134 [(2R,4R)-4-fluoro-2- 311 1.22-1.42 (m, 2 H), 1.56-1.39 (m, 8 H),1.89-2.10 (ES+), at 3.72 min, (methoxycarbonyl) (m, 3 H), 2.31-2.48 (m,2 H), 2.55-2.68 (m, 1 H), UV active pyrrolidin-1-yl]piperidin- 2.68-2.94(m, 3 H), 3.07 (d, J = 11.4 Hz, 1 H), 1-yl}-6- 3.10-3.19 (m, 2 H), 3.19-3.28 (m, 2 H), 3.51 (dd, azaspiro[3.4]octane-6- J = 9.9, 4.3 Hz, 1 H),3.61 (s, 3 H), 3.99 (q, J = 7.1 carboxylate Hz, 2 H), 5.02-5.30 (m, 1 H)2- Isomer 2: ethyl 2-{4- 2 and aw (300 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.1Hz, 3 H), E m/z 412 (M + H)⁺ 135 [(2R,4S)-4-fluoro-2- 312 1.21-1.42 (m,2 H), 1.57-1.38 (m, 8 H), 1.89-2.01 (ES+), at 3.96 min,(methoxycarbonyl) (m, 2 H), 2.02-2.31 (m, 2 H), 2.34-2.46 (m, 1 H), UVactive pyrrolidin-1-yl]piperidin- 2.55-2.65 (m, 1 H), 2.65-2.79 (m, 2H), 2.85-3.05 1-yl}-6- (m, 1 H), 3.07-3.22 (m, 3 H), 3.22-3.27 (m, 2 H),azaspiro[3.4]octane-6- 3.61 (s, 3 H), 3.76 (t, J = 7.0 Hz, 1 H), 3.99(q, J = carboxylate 7.1 Hz, 2 H), 5.08-5.40 (m, 1 H) 2- Isomer 2: ethyl2-{4- Example ar (300 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.1 Hz, 3 H), E m/z384 (M + H)⁺ 136 [(2R,4R)-4-fluoro-2- 2-134 1.25-1.51 (m, 2 H),1.56-1.39 (m, 8 H), 1.89-2.06 (ES⁺), at 3.20 min, (hydroxymethyl) (m, 3H), 2.34-2.45 (m, 2 H), 2.58-2.68 (m, 2 H), UV inactivepyrrolidin-1-yl]piperidin- 2.70-2.82 (m, 3 H), 2.82-2.94 (m, 1 H),2.96-3.10 1-yl}-6- (m, 1 H), 3.11-3.20 (m, 3 H), 3.39-3.49 (m, 2 H),azaspiro[3.4]octane-6- 3.99 (q, J = 7.2 Hz, 2 H), 4.39 (t, J = 5.7 Hz, 1H), carboxylate 4.95-5.24 (m, 1 H) 2- Isomer 2: ethyl 2-{4- Example ar(300 MHz, DMSO-d₅) δ: 1.16 (t, J = 7.1 Hz, 3 H), E m/z 384 (M + H)⁺ 137[(2R,4S)-4-fluoro-2- 2-135 1.26-1.45 (m, 2 H), 1.57-1.88 (m, 8 H),1.91-2.09 (ES⁺), at 3.33 min, (hydroxymethyl) (m, 3 H), 2.56-2.65 (m, 4H), 2.69-2.84 (m, 3 H), UV active pyrrolidin-1-yl]piperidin- 2.99-3.17(m, 4 H), 3.18-3.24 (m, 1 H), 3.36-3.45 1-yl}-6- (m, 2 H), 3.99 (q, J =7.1 Hz, 2 H), 4.35 (t, J = 5.7 azaspiro[3.4]octane-6- Hz, 1 H),4.98-5.25 (m, 1 H) carboxylate 2- Isomer 2: ethyl 2-{4-[(2S)- 91 and r(400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3H), E m/z 418 (M + H)⁺ 1381-(5-methyl-1,3,4- 127 1.28-1.45 (m, 1H), 1.58-1.68 (m, 2H), 1.69-1.86(ES+), at 2.57 min, oxadiazol-2-yl)pyrrolidin- (m, 3H), 1.86-2.01 (m,8H), 2.07-2.13 (m, 2H), UV active 2-yl]piperidin-1-yl}-6- 2.37 (s, 3H),2.67-2.98 (m, 3H), 3.24-3.42 (m, azaspiro[3.4]octane-6- 4H), 3.43-3.57(m, 3H), 3.78-3.88 (m, 1H), 4.09 carboxylate. (q, J = 7.3 Hz, 2H). 3-1Isomer 1: methyl 2-[4-(2- 3 and 65 b (400 MHz, DMSO-d₆) δ: 1.35-1.51 (m,2H), 1.66- G m/z 346 (M + H)⁺ yl)piperidin-1-yl]-6- 1.83 (m, 8H),1.98-2.09 (m, 2H), 2.40-2.72 (m, (ES+), at 4.34 min,oxo-1,2-dihydropyridin-3- 2H), 2.81-2.91 (m, 2H), 3.15-3.43 (m, 4H),3.57 UV active azaspiro[3.4]octane-6- (s, 3H), 6.12 (dd, J = 6.5 and 6.5Hz, 1H), 7.16- carboxylate 7.26 (m, 2H), NH not observed 3-1 Isomer 2:methyl 2-[4-(2- 3 and 65 b (400 MHz, DMSO-d₆) δ: 1.34-1.52 (m, 2H),1.66- G m/z 346 (M + H)⁺ oxo-1,2-dihydropyridin-3- 1.93 (m, 8H),1.94-2.11 (m, 2H), 2.45-2.75 (m, (ES+), at 4.43 min,yl)piperidin-1-yl]-6- 2H), 2.78-2.94 (m, 2H), 3.09-3.21 (m, 2H), 3.21-UV active azaspiro[3.4]octane-6- 3.44 (m, 2H), 3.56 (s, 3H), 6.13 (dd, J= 6.5 and carboxylate 6.5 Hz, 1H), 7.18-7.33 (m, 2H), NH not observed3-2 Isomer 1: ethyl 2-[4-(2- 2 and 65 b (400 MHz, DMSO-d₆) δ: 0.99-1.23(m, 3H), 1.30- F m/z 360 (M + H)⁺ oxo-1,2-dihydropyridin-3- 1.49 (m,2H), 1.59-1.84 (m, 6H), 1.95-2.11 (m, (ES+), at 1.54 min,yl)piperidin-1-yl]-6- 2H), 2.45-2.74 (m, 5H), 2.75-2.89 (m, 2H), 3.15-UV active azaspiro[3.4]octane-6- 3.31 (m, 3H), 3.93-4.07 (m, 2H), 6.18(dd, J = 6.5 carboxylate and 6.5 Hz, 1H), 7.21 (d, J = 6.5 Hz, 1H), 7.25(d, J = 6.5 Hz, 1H), NH not observed 3-2 Isomer 2: ethyl 2-[4-(2- 2 and65 b (400 MHz, DMSO-d₅) δ: 1.08-1.27 (m, 3H), 1.32- F m/z 360 (M + H)⁺oxo-1,2-dihydropyridin-3- 1.58 (m, 2H), 1.59-1.76 (m, 2H), 1.76 (m, 4H),(ES+), at 1.58 min, yl)piperidin-1-yl]-6- 1.93-2.20 (m, 2H), 2.45-2.97(m, 5H), 3.08-3.20 UV active azaspiro[3.4]octane-6- (m, 2H), 3.22-3.36(m, 2H), 3.95-4.11 (m, 2H), carboxylate 6.17 (dd, J = 6.5 and 6.5 Hz,1H), 7.21(d, J = 6.5 Hz, 1H), 7.25 (d, J = 6.5 Hz, 1H), NH not observed3-3 Isomer 2: 2-fluoroethyl 2- 4 and 65 b (400 MHz, DMSO-d₅) δ:1.35-1.57 (m, 2H), 1.58- F m/z 378 (M + H)⁺ [4-(2-oxo-1,2- 1.92 (m, 5H),1.91-2.13 (m, 2H), 2.32-3.02 (m, (ES+), at 1.57 min, dihydropyridin-3-7H), 3.20-3.44 (m, 4H), 4.07-4.32 (m, 2H), 4.47- UV activeyl)pipendin-1-yl]-6- 4.72 (m, 2H), 6.13 (dd, J = 6.5 and 6.5 Hz, 1H),azaspiro[3.4]octane-6- 7.18-7.43 (m, 2H), 11.49 (s, 1H) carboxylate 3-4Isomer 2: ethyl 2-[4-(3- 2 and 18 b (400 MHz, CDCl₃) δ: 1.21-1.29 (m,3H), 1.75- C m/z 360 (M + H)⁺ hydroxypyridin-2- 2.38 (m, 12H), 2.87-3.23(m, 4H), 3.24-3.43 (m, (ES+), at 1.29 min, yl)piperidin-1-yl]-6- 4H),4.05-4.21 (m, 2H), 6.97-7.06 (m, 1H). 7.12- UV activeazaspiro[3.4]octane-6- 7.21 (m, 1H), 8.02-8.10 (m, 1H), OH not observedcarboxylate 3-5 Isomer 2: 2-fluoroethyl 2- 4 and 66 b (400 MHz, DMSO-d₆)δ: 1.48-2.08 (m, 11H), F m/z 392 (M + H)⁺ [4-(2-methoxypyridin-3-2.65-2.79 (m, 2H), 2.84-2.94 (m, 2H), 3.14-3.24 (ES+), at 1.73 min,yl)piperidin-1-yl]-6- (m, 2H), 3.26-340 (m, 3H), 3.86 (m, 3H), 4.15- UVactive azaspiro[3.4]octane-6- 4.21 (m, 1H), 4.21-4.30 (m, 1H), 4.48-4.57(m, carboxylate 1H), 4.61-4.69 (m, 1H), 6.94 (dd, J = 7.0 & 5.0 Hz, 1H),7.58 (d, J = 7.0 Hz, 1H), 8.01 (d, J = 5.0, 1H) 3-6 Isomer 2: ethyl2-[4-(6- 2 and 71 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3H), Fm/z 388 (M + H)⁺ methoxy-4-methylpyridin- 1.48-1.89 (m, 9H), 1.93-2.04(m, 2H), 2.24 (s, (ES+), at 1.73 min, 3-yl)piperidin-1-yl]-6- 3H),2.41-2.55 (m, 3H), 2.82-2.95 (m, 2H), 3.05- UV activeazaspiro[3.4]octane-6- 3.23 (m, 2H), 3.23-3.36 (m, 2H), 3.77 (m, 3H),carboxylate 3.99 (q, J = 7.0 Hz, 2H), 6.60 (s, 1H), 7.94 (s, 1H) 3-7Isomer 2: ethyl 2-[4-(6- 2 and 72 b (400 MHz, DMSO-d₅) δ: 1.18 (t, J =7.0 Hz, 3H), F m/z 388 (M + H)⁺ methoxy-5-methylpyridin- 1.54-2.10 (m,12H), 2.12 (s, 3H), 2.70-3.10 (m, (ES+), at 1.77 min,3-yl)piperidin-1-yl]-6- 2H), 3.15-3.23 (m, 2H), 3.24-3.36 (m, 2H), 3.37-UV active azaspiro[3.4]octane-6- 3.52 (m, 2H), 3.84 (m, 3H), 4.00 (q, J= 7.0 Hz, carboxylate 2H), 7.43 (s, 1 H), 7.86 (s, 1H) 3-8 Isomer 2:ethyl 2-[4-(2- 1 and 70 d ¹H NMR (400 MHz, CD₃OD) δ: 1.18-1.32 (m, 3 Bm/z 360 (M + H)⁺ aminopyrimidin-4- H), 1.68-2.03 (m, 10 H), 2.07-2.18(m, 2 H), 2.49 (ES+), at 2.98 min, yl)piperidin-1-yl]-6- (t, J = 11.7Hz, 1 H), 2.80 (quin, J = 8.0 Hz, 1 H), UV active azaspiro[3.4]octane-6-3.00 (d, J = 11.3 Hz, 2 H), 3.33-3.45 (m, 4 H), 4.09 carboxylate (q, J =7.0 Hz, 2 H), 6.56 (d, J = 5.5 Hz, 1 H), 8.12 (d, J = 5.5 Hz, 1 H), twoNH not observed 3-9 Isomer 2: ethyl 2-[4-(4- 2 and 26 as (400 MHz,CD₃OD) δ: 1.23-1.28 (m, 3H), 1.83- C m/z 360 (M + H)⁺ aminopyrimidin-2-1.99 (m, 10H), 2.07-2.21 (m, 2H), 2.52-2.68 (m, (ES+), at 1.56 min,yl)piperidin-1-yl]-6- 1H), 2.73-2.90 (m, 1H), 2.96-3.07 (m, 2H), 3.28 UVactive azaspiro[3.4]octane-6- (s, 2H), 3.36-3.46 (m, 2H), 4.09-4.13 (m,2H), carboxylate 6.33 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 2 ×NH not observed 3-10 Isomer 1: ethyl 2-[4- 2 and 14 at (400 MHz, CDCl₃)δ: 1.17-1.37 (m, 4H), 1.45-1.72 B m/z 369 (M + H)⁺ cyano-4-(pyridin-2-(m, 2H), 1.75-2.02 (m, 3H), 2.06-2.51 (m, 7H), (ES+), at 3.33 min,yl)piperidin-1-yl]-6- 2.72-3.15 (m, 2H), 3.26-3.48 (m, 4H), 4.06-4.22 UVactive azaspiro[3.4]octane-6- (m, 2H), 7.21-7.32 (m, 1H), 7.55 (d, J =3.2 Hz, carboxylate 1H), 7.74 (dd, J = 7.2 + 7.2 Hz, 1H), 8.56-8.68 (m,1H). 3-10 Isomer 2: ethyl 2-[4- 2 and 14 at (400 MHz, CDCl₃) δ:1.16-1.39 (m, 4H), 1.48-1.70 B m/z 369 (M + H)⁺ cyano-4-(pyridin-2- (m,2H), 1.78-2.47 (m, 10H), 2.74-3.09 (m, 2H), (ES+), at 3.40 min,yl)piperidin-1-yl]-6- 3.20-3.50 (m, 4H), 4.03-4.20 (m, 2H), 7.20-7.32 UVactive azaspiro[3.4]octane-6- (m, 1H), 7.48-7.61 (m, 1H), 7.67-7.82 (m,1H), carboxylate 8.55-8.69 (m, 1H). 3-11 Isomer 2: ethyl 2-[4-(2- 2 andb (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3 H), F m/z 388 (M + H)⁺methoxy-4-methylpyridin- 134 1.40 (d, J = 12.2 Hz, 2 H), 1.67-1.94 (m, 6H), 2.00 (ES⁺) at 1.86 min, 3-yl)piperidin-1-yl]-6- (ddd, J = 9.2, 7.1,2.6 Hz, 2 H), 2.11-2.26 (m, 2 H), UV active azaspiro[3.4]octane-6- 2.29(s, 3 H), 2.61-2.70 (m, 1 H), 2.73-2.81 (m, 1 carboxylate H), 2.86 (d, J= 11.0 Hz, 2 H), 3.26-3.33 (m, 2 H), 3.84 (s, 3 H), 4.01 (q, J = 7.0 Hz,2 H), 4.11 (q, J = 5.2 Hz, 2 H), 8.78 (d, J = 5.2 Hz, 1 H), 7.85 (d, J =4.9 Hz, 1 H). 3-12 Isomer 2: ethyl 2-[4-(2- 2 and b (400 MHz, DMSO-d₆)δ: 1.14-1.19 (m, 4H), 1.57 G m/z 388 (M + H)⁺ methoxy-5-methylpyridin-129 (d, J = 9.6 Hz, 2H), 1.66 (s, 3H), 1.77-1.85 (m, (ES⁺) at 7.10 min,3-yl)piperidin-1-yl]-6- 4H), 1.86 (s, 2H), 2.01 (d, J = 7.6 Hz, 2H),2.19 (s, UV active azaspiro[3.4]octane-6- 3H), 2.88 (d, J = 10.0 Hz,2H), 3.16 (d, J = 5.2 Hz, carboxylate 2H), 3.26-3.34 (m, 2H), 3.82 (s,3H), 4.00 (d, J = 6.8 Hz, 2H), 7.40 (s, 1H), 7.80 (s, 1H). 3-13 Isomer2: ethyl 2-[4-(6- 2 and b (400 MHz, DMSO-d₆) δ: 1.16 (s, 3 H), 1.57-1.89G m/z 374 (M + H)⁺ methoxypyridin-2- 141 (m, 11 H), 1.93-2.07 (m, 2 H),2.63-2.70 (m, 1 H), (ES⁺) at 7.15 min, yl)piperidin-1-yl]-6- 2.86-2.95(m, 2H), 3.08-3.18 (m, 2 H), 3.25-3.45 UV active azaspiro[3.4]octane-6-(m, 2 H), 3.83 (s, 3 H), 4.00 (d, J = 4.0 Hz, 2 H), carboxylate 6.60 (d,J = 7.6 Hz, 1 H), 6.80-6.90 (m, 1 H), 7.55- 7.70 (m, 1 H). 3-14 Isomer1: ethyl 2-[4-(4- 2 and b (400 MHz, CD₃OD) δ: 0.91 (d, J = 7.3 Hz, 4 H),H m/z 374 (M + H)⁺ methyl-2-oxo-1,2- 146 1.04-1.65 (m, 8 H) 1.84-2.21(m, 4 H), 2.31 (s, 3 (ES⁺) at 3.85 min, dihydropyridin-3- H), 2.58 (d, J= 13.7 Hz, 2 H), 2.77-3.09 (m, 3 H), UV active yl)piperidin-1-yl]-6-3.25-3.47 (m, 2 H), 4.06-4.19 (m, 2 H), 6.22 (d, azaspiro[3.4]octane-6-J = 6.7 Hz, 1 H), 7.17 (d, J = 6.4 Hz, 1 H), NH not carboxylateobserved. 3-14 Isomer 2: ethyl 2-[4-(4- methyl-2-oxo-1,2- 2 and b (400MHz, CD₃OD) δ: 0.92 (d, J = 7.3 Hz, 4 H), I m/z 374 (M + H)⁺dihydropyridin-3- 146 1.18-1.60 (m, 8 H), 1.88-2.25 (m, 4 H), 2.31 (s, 3(ES⁺) at 4.04 min, yl)piperidin-1-yl]-6- H), 2.50-3.20 (m, 5 H),3.28-3.50 (m, 2 H), 4.12 UV active azaspiro[3.4]octane-6- (q, J = 7.0Hz, 2 H), 6.23 (d, J = 6.7 Hz, 1 H), 7.18 carboxylate (d, J = 6.4 Hz, 1H), NH not observed. 3-15 Isomer 1: ethyl 2-[4-(5- 2 and b ¹H NMR (400MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 E m/z 374 (M + H)⁺ methyl-2-oxo-1,2-143 Hz, 3H), 1.40-1.62 (m, 2H), 1.65-1.78 (m, 4H), (ES⁺) at 3.27 min,dihydropyridin-3- 1.78-1.95 (m, 5H), 1.95-2.09 (m, 5H), 2.57-2.73 UVactive yl)piperidin-1-yl]-6- (m, 1H), 2.81-3.06 (m, 2H), 3.08-3.23 (m,2H), azaspiro[3.4]octane-6- 3.24-3.43 (m, 2H), 4.00 (q, J = 7.0 Hz, 2H),7.00 carboxylate (s, 1H), 7.10 (s, 1H), 11.30 (s, 1H). 3-15 Isomer 2:ethyl 2-[4-(5- methyl-2-oxo-1,2- 2 and b (400 MHz, DMSO-d₆) δ: 1.18 (td,J = 7.1, 2.9 Hz, E m/z 374 (M + H)⁺ dihydropyridin-3- 143 3 H),1.38-1.96 (m, 10 H), 2.04-2.28 (m, 3 H), (ES⁺) at 3.33 min,yl)piperidin-1-yl]-6- 2.57-2.77 (m, 1 H), 2.84-3.10 (m, 2 H), 3.12-3.45UV active azaspiro[3.4]octane-6- (m, 7 H), 4.01 (q, J = 7.2 Hz, 2 H),7.00 (s, 1 H), carboxylate 7.10 (s, 1 H), 11.31 (br. s., 1 H). 3-16Isomer 2: ethyl 2-[4-(2- 2 and b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 6.9Hz, 3 H), I m/z 360 (M + H)⁺ oxo-1,2-dihydropyridin-4- 154 1.41-2.09 (m,12 H), 2.28-2.44 (m, 1 H), 2.61-2.76 (ES⁺) at 3.26 min,yl)piperidin-1-yl]-6- (m, 1 H), 2.86 (d, J = 10.7 Hz, 1 H), 3.03-3.44(m, UV active azaspiro[3.4]octane-6- 5 H), 4.00 (q, J = 7.0 Hz, 2 H),6.00 (d, J = 7.0 Hz, carboxylate 1 H), 5.13 (d, J = 8.5 Hz, 1 H), 7.35(dd, J = 9.2, 7.0 Hz, 1 H), 11.20-11.58 (m, 1 H). 4-1 Isomer 2: ethyl2-(2-oxo- 2 and 69 b (400 MHz, DMSO-d₆) δ: 1.17 (t, J = 6.7 Hz, 3 H), Gm/z 364 (M + H)⁺ 3,4′-bipiperidin-1′-yl)-6- 1.22-2.11 (m, 18 H),2.57-2.69 (m, 1 H), 2.80 (t, (ES⁺) at 4.86 min, azaspiro[3.4]octane-6- J= 11.6 Hz, 2 H), 2.96-3.15 (m, 2 H), 3.16-3.30 UV inactive carboxylate(m, 4 H), 4.01 (q, J = 7.0 Hz, 2 H), 7.39 (br. s., 1 H). 4-1 Isomer 3:ethyl 2-(2-oxo- 2 and 69 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.0 Hz, 3H), G m/z 364 (M + H)⁺ 3,4′-bipiperidin-1′-yl)-6- 1.21-2.12 (m, 18 H),2.55-2.70 (m, 1 H), 2.72-2.86 (ES⁺) at 4.95 min, azaspiro[3.4]octane-6-(m, 2 H), 3.00-3.17 (m, 4 H), 3.27 (d, J = 7.0 Hz, 2 UV inactivecarboxylate H), 4.00 (q, J = 7.2 Hz, 2 H), 7.39 (br. s., 1 H). 4-1Isomer 4: ethyl 2-(2-oxo- 2 and 69 b (400 MHz, DMSO-d₆) δ: 1.16 (t, J =7.0 Hz, 3 H), G m/z 364 (M + H)⁺ 3,4′-bipiperidin-1′-yl)-6- 1.21-1.89(m, 14 H), 1.89-2.02 (m, 3 H), 2.02-2.12 (ES⁺) at 4.97 min,azaspiro[3.4]octane-6- (m, 1 H), 2.55-2.64 (m, 1 H), 2.65-2.85 (m, 2 H),UV inactive carboxylate 2.98-3.18 (m, 4 H), 3.20-3.39 (m, 2 H), 4.00 (q,J = 7.2 Hz, 2 H), 7.39 (br. s., 1 H). 4-2 Isomer 4: methyl 2-(2- 3 and69 b (400 MHz, DMSO-d₅) δ: 1.07-2.20 (m, 18 H), G m/z 350 (M + H)⁺oxo-3,4′-bipiperidin-1′-yl)- 2.99-3.21 (m, 4 H), 3.23-3.43 (m, 5 H),3.56 (s, 3 (ES⁺) at 3.23 min, 6-azaspiro[3.4]octane-6- H), 7.44 (br. s.,1 H). UV inactive carboxylate 4-3 Isomer 2: ethyl 2-(4- 2 and b (400MHz, CD₃OD) δ: 0.98 (d, J = 7.0 Hz, 2 H), E m/z 378 (M + H)⁺methyl-2-oxo-3,4′- 147 1.19-1.70 (m, 7 H), 1.71-1.34 (m, 2 H), 1.84-2.10(ES⁺) at 3.75 min, bipiperidin-1′-yl)-6- (m, 6 H), 2.11-2.43 (m, 4 H),2.83-3.09 (m, 2 H), UV inactive azaspiro[3.4]octane-6- 3.23-3.45 (m, 9H), 4.13 (q, J = 7.0 Hz, 2 H). carboxylate 4-4 Isomer 1: ethyl 2-(5- 2and b (400 MHz, CDCl₃) δ: 1.02 (d, J = 6.7 Hz, 2 H), I m/z 378 (M + H)⁺methyl-2-oxo-3,4′- 144 1.24-1.35 (m, 3 H), 1.48-2.42 (m, 14 H),2.76-3.30 (ES⁺) at 3.59 min, bipiperidin-1′-yl)-6- (m, 10 H), 3.38 (d, J= 19.8 Hz, 3 H), 4.14 (q, J = UV inactive azaspiro[3.4]octane-6- 7.0 Hz,2 H), 6.38 (br. s., 1 H). carboxylate 4-4 Isomer 2: ethyl 2-(5- 2 and b(400 MHz, CDCl₃) δ: 1.03 (d, J = 6.4 Hz, 2 H), I m/z 378 (M + H)⁺methyl-2-oxo-3,4′- 144 1.22-1.36 (m, 3 H), 1.48-2.19 (m, 14 H),2.20-2.45 (ES⁺) at 3.67 min, bipiperidin-1′-yl)-6- (m, 3 H), 2.79-3.67(m, 10 ), 4.13 (q, J = 6.7 Hz, 2 UV inactive azaspiro[3.4]octane-6- H),6.58 (br. s., 1 H) carboxylate 4-5 Isomer 2: ethyl 2-(1-ethyl- Exampleau (400 MHz, CD₃OD) δ: 1.13 (t, J = 7.2 Hz, 3 H), I m/z 392 (M + H)⁺2-oxo-3,4′-bipiperidin-1′- 4-1 and 1.19 (t, J = 7.2 Hz, 3 H), 1.23-2.39(m, 17 H), (ES⁺) at 3.91 min, yl-6-azaspiro[3.4]octane- 114 2.63-3.04(m, 3 H), 3.25-3.52 (m, 9 H), 4.11 (q, UV inactive 6-carboxylate J = 7.2Hz, 2 H). 4-6 Isomer 2: ethyl 2-[2-oxo- Example au (400 MHz, CD₃OD) δ:1.14 (dd, J = 7.0, 5.2 Hz, 6 E m/z 406 (M + H)⁺ 1-(propan-2-yl)-3,4′-4-1 and H), 1.21-1.74 (m, 8 H), 1.79-2.01 (m, 7 H), 2.08- (ES⁺) at 4.12min, bipiperidin-1′-yl]-6- 156 2.22 (m, 3 H), 2.35 (ddd, J = 10.5, 6.6,4.3 Hz, 1 UV inactive azaspiro[3.4]octane-6- H), 2.74-3.08 (m, 3 H),3.10-3.23 (m, 1 H), 3.24- carboxylate 3.46 (m, 7 H), 4.12 (q, J = 7.2Hz, 2 H), 4.78 (sept, J = 6.8 Hz, 1 H). 4-7 Isomer 2: ethyl 2-[4-(2- 2and at (400 MHz, CDCl₃) δ: 1.22 (td, J = 7.0, 3.9 Hz, 3 B m/z 366 (M +H)⁺ oxo-1,3-oxazinan-3- 132 H), 1.66-1.76 (m, 4 H), 1.76-1.92 (m, 6 H),1.92- (ES⁺), at 2.35 min, yl)piperidin-1-yl]-6- 2.12 (m, 4 H), 2.58-2.76(m, 1 H), 2.91 (d, J = 10.2 UV inactive azaspiro[3.4]octane- Hz, 2 H),3.17-3.31 (m, 4 H), 3.31-3.44 (m, 2 H), 6-carboxylate 4.09 (q, J = 7.0Hz, 2 H), 4.14-4.29 (m, 3 H). 4-8 Isomer 1: ethyl 2-[4-(2- 2 and av (400MHz, CDCl₃) δ: 1.24 (td, J = 7.0, 3.1 Hz, 3 E m/z 365 (M + H)⁺oxotetrahydropyrimidin- 137 H), 1.58-1.74 (m, 4 H), 1.74-2.01 (m, 8 H),2.02- (ES⁺), at 2.68 min, 1(2H)-yl)piperidin-1-yl]- 2.21 (m, 2 H),2.52-2.73 (m, 1 H), 2.78-3.03 (m, 2 UV inactive 6-azaspiro[3.4]octane-6-H) 3.10-3.41 (m, 8 H), 4.10 (q, J = 7.3 Hz, 2 H), carboxylate 4.22-4.42(m, 1 H), 4.67-4.82 (m, 1 H). 4-8 Isomer 2: ethyl 2-[4-(2- 2 and av (400MHz, CDCl₃) δ: 1.17-1.31 (m, 3H), 1.49-1.77 E m/z 365 (M + H)⁺oxotetrahydropyrimidin- 137 (m, 4H), 1.77-1.97 (m, 7H), 1.97-2.19 (m,3H), (ES⁺), at 2.81 min, 1(2H)-yl)piperidin-1-yl]- 2.52-3.02 (m, 3H),3.09-3.31 (m, 6H), 3.31-3.48 UV inactive 6-azaspiro[3.4]octane-6- (m,2H), 4.01-4.17 (m, 2H), 4.23-4.46 (m, 1H), carboxylate 4.57-4.92 (m,1H). 4-9 Mixture of diastereomers: 2 and av (400 MHz, CDCl₃) δ:0.96-1.12 (m, 5 H), 1.25 (td, B m/z, 393 (M + H)⁺ ethyl2-[4-(5,5-dimethyl- 149 J = 7.0, 3.9 Hz, 3 H), 1.48-1.96 (m, 8 H),1.96-2.71 (ES⁺), at 2.67 min, 2-oxotetrahydropyrimidin- (m, 5 H),2.79-3.00 (m, 5 H), 3.16-3.60 (m, 5 H), UV inactive1(2H)-yl)piperidin-1-yl]- 4.03-4.19 (m, 2 H), 4.25-4.73 (m, 2 H).6-azaspiro[3.4]octane-6- carboxylate 4-10 Isomer 2: ethyl 2-(1,4′- 2 andaw (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 350 (M + H)⁺bipiperidin-1′-yl)-6- 276 1.28-1.50 (m, 8H), 1.54-1.67 (m, 4 H),1.67-1.86 (ES⁺), at 3.62 min, azaspiro[3.4]octane-6- (m, 4 H), 1.86-2.01(m, 2 H), 2.34-2.44 (m, 3 H), UV inactive carboxylate 2.50-2.62 (m, 2H), 2.76 (d, J = 11.7 Hz, 2 H), 3.10 (d, J = 6.2 Hz, 2 H), 3.19-3.26 (m,3 H), 3.96 (q, J = 7.0 Hz, 2 H) 4-11 Isomer 2: ethyl 2-[4- 2 and aw (400MHz, DMSO-d₆) δ: 1.14 (t, J = 7.0 Hz, 3 H), E m/z 352 (M + H)⁺(morpholin-4-yl)peridin-1- 272 1.23-1.37 (m, 2 H), 1.52-1.83 (m, 7 H),1.92-2.12 (ES⁺), at 2.70 min, yl]-6-azaspiro[3.4]octane- (m, 3 H),2.36-2.45 (m, 6 H), 2.52-2.57 (m, 2 H), UV inactive 6-carboxylate 2.76(d, J = 10.2 Hz, 2 H), 3.13-3.26 (m, 3 H), 3.48-3.57 (m, 3 H), 3.98 (q,J = 7.0 Hz, 2 H) 4-12 Isomer 2: ethyl 2-[4- 2 and aw (400 MHz, DMSO-d₆)δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 368 (M + H)⁺ (thiomorpholin-4- 2681.39 (q, J = 10.9 Hz, 2 H), 1.49-1.66 (m, 5 H), (ES⁺), at 3.18 min,yl)piperidin-1-yl]-6- 1.66-1.85 (m, 5 H), 1.89-2.00 (m, 3 H), 2.22 (t, J= UV inactive azaspiro[3.4]octane-6- 12.1 Hz, 2 H), 2.68-2.74 (m, 5 H),2.78 (d, J = 10.5 carboxylate Hz, 2 H), 3.11 (d, J = 5.9 Hz, 2 H),3.20-3.27 (m, 2 H), 3.97 (q, J = 7.0 Hz, 2 H) 4-13 Isomer 2: ethyl2-(3,3- 2 and aw (300 MHz, DMSO-d₈) δ: 1.16 (t, J = 7.1 Hz, 3 H), E m/z386 (M + H)⁺ difluoro-1,4′-bipiperidin- 280 1.29-1.48 (m, 2 H),1.57-1.91 (m, 9 H), 1.92-2.00 (ES⁺), at 3.64 min, 1′-yl)-6- (m, 2 H),2.37-2.49 (m, 4 H), 2.53-2.71 (m, 5 H), UV inactiveazaspiro[3.4]octane-6- 2.74-2.86 (m, 2 H), 3.06-3.22 (m, 4 H), 3.99 (q,carboxylate J = 7.0 Hz, 2 H) 4-14 Isomer 2: ethyl 2-(4,4- 2 and aw (400MHz, DMSO-d₅) δ: 1.13 (t, J = 7.0 Hz, 3 H), E m/z 386 (M + H)⁺difluorro-1,4′-bipiperidin- 266 1.28-1.44 (m, 2H), 1.56-1.67 (m, 4 H)1.67-1.75 (ES⁺), at 3.49 min, 1′-yl)-6- (m, 2H), 1.75-2.01 (m, 8 H),2.20-2.30 (m, 1 H), UV inactive azaspiro[3.4]octane-6- 2.51-2.63 (m, 5H), 2.77 (d, J = 11.7 Hz, 2 H), 3.11 carboxylate (d, J = 6.2 Hz, 2 H),3.24 (q, J = 6.9 Hz, 2 H), 3.97(q, J = 7.0 Hz, 2 H) 4-15 Isomer 2:methyl (2R)-1′- 2 and aw (400 MHz, DMSO-d₈) δ: 1.13 (t, J = 7.0 Hz, 3H), E m/z 408 (M + H)⁺ [6-(ethoxycarbonyl)-6- 290 1.23-1.50 (m, 7 H),1.57-1.67 (m, 5 H), 1.67-1.87 (ES⁺), at 3.86 min,azaspiro[3.4]oct-2-yl]- (m, 5 H), 1.95 (t, J = 8.4 Hz, 2 H), 2.38-2.42(m, 1 UV inactive 1,4′-bipiperidine-2- H), 2.70-2.94 (m, 3 H), 3.11 (d,J = 5.9 Hz, 2 H), carboxylate 3.24 (q, J = 6.8 Hz, 3 H), 3.42-3.45 (m, 1H), 3.58 (s, 3 H), 3.97 (q, J = 7.0 Hz, 2 H) 4-16 Isomer 2: ethyl2-[(2R)-2- 2 and ax (400 MHz, CDCl₃) δ: 1.22 (t, J = 6.8 Hz, 3H), M m/z407 (M + H)⁺ (methylcarbamoyl)-1,4′- 223 1.41-1.50 (m, 2H), 1.61-1.75(m, 4H), 1.81-1.95 (ES+), at 1.69 min, bipiperidin-1′-yl]-6- (m, 6H),2.51-2.61 (m, 1H), 2.70-2.75 (m, 1H), UV inactive azaspiro[3.4]octane-6-2.82 (d, J = 4.6 Hz, 3H), 2.95-3.45 (m, 11H), 3.10- carboxylate 3.27 (m,4H), 4.12 (q, J = 6.8 Hz, 2H), 7.06 (br.s., 1H). 4-17 Isomer 2: ethyl2-[(2R)-2- 2 and aw (400 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.0 Hz, 3 H), Em/z 421 (M + H)⁺ (dimethylcarbamoyl)-1,4′- 283 1.29-1.41 (m, 2 H),1.43-1.53 (m, 3 H), 1.53-1.66 (ES⁺), at 4.13 min, bipiperidin-1′-yl-6-(m, 5 H), 1.66-1.74 (m, 2 H), 1.74-1.87 (m, 3 H), UV inactiveazaspiro[3.4]octane-6- 1.87-1.99 (m, 3 H), 2.41-2.45 (m, 3 H), 2.76 (s,6 carboxylate H), 3.10 (d, J = 6.2 Hz, 4 H), 3.12-3:15 (m, 4 H), 3.97(q, J = 7.0 Hz, 2 H) 4-18 Isomer 2: ethyl 2-[(2s)-2- 2 and ax (400 MHz,CDCl₃) δ: 1.25 (t, J = 6.8 Hz, 3H), M m/z 407 (M + H)⁺(methylcarbamoyl)-1,4′- 225 1.41-1.50 (m, 2H), 1.61-1.75 (m, 4H),1.81-1.95 (ES+), at 1.67 min, bipiperidin-1′-yl]-6- (m, 6H), 2.51-2.61(m, 1H), 2.70-2.75 (m, 1H), UV inactive azaspiro[3.4]octane-6- 2.82 (d,J = 4.6 Hz, 3H), 2.95-3.45 (m, 11H), 3.10- carboxylate 3.27(m, 4H), 4.12(q, J = 8.8 Hz, 2H), 7.22 (br.s., 1H). 4-19 Isomer 2: ethyl 2-(1- 222,229 y (400 MHz, CDCl₃) δ: 1.10- 1.15 (m, 3H), 1.22- O m/z 406 (M + H)⁺propanoyl-2,4′- and 230 1.25 (m, 3H), 1.34-1.54 (m, 4H), 1.55-1.68 (m,(ES+), at 4.48 min, bipiperidin-1-yl)-6- 4H), 1.70-1.80 (m, 3H),1.81-1.90 (m, 4H), 1.98- UV inactive azaspiro[3.4]octane-6- 2.20 (m,6H), 2.27-2.40 (m, 2H), 2.42-3.10 (m, carboxylate 3H), 3.22-3.34 (m,2H), 3.34-3.45 (m, 2H), 4.05- 4.15 (m, 2H), 4.53-4.64 (m, 1H). 4-20Isomer 2: ethyl 2-[1- 57 and m (400 MHz, CDCl₃) δ: 1.22-1.27 (m, 3H),1.31-1.47 O m/z 407 (M + H)⁺ (methylcarbamoyl)-2,4′- 229 (m, 3H),1.48-1.62 (m, 5H), 1.72-1.79 (m, 2H), (ES+), at 4.29 min,bipiperidin-1′-yl]-6- 1.82-1.91 (m, 4H), 2.02-2.12 (m, 5H), 2.61-2.82 UVinactive azaspiro[3.4]octane-6- (m, 5H), 2.90-3.06 (m, 2H), 3.25-3.33(m, 2H), carboxylate 3.34-3.44 (m, 2H), 3.48-3.64 (m, 1H), 3.88-4.00 (m,1H), 4.05-4.13 (m, 2H), 4.37 (br.s., 1H). 5-1 Isomer 2: ethyl 2-[4-(2-2, 214 ay (400 MHz, CD₃OD) δ: 1.24 (t, J = 7.0 Hz, 3 H), E m/z 378 (M +H)⁺ oxoazepan-1-yl)piperidin- and 322 1.52-1.79 (m, 10 H), 1.80-1.99 (m,6 H), 2.04-2.17 (ES+), at 2.85 min, 1-yl]-6- (m, 2 H), 2.48-2.61 (m, 2H), 2.72-2.88 (m, 1 H), UV inactive azaspiro[3.4]octane-6- 2.96 (d, J =11.7 Hz, 2 H), 3.26 (s, 2 H), 3.33-3.46 carboxylate (m, 4 H), 4.09 (q, J= 7.0 Hz, 2 H), 4.40 (tt, J = 12.01, 4.20 Hz, 1 H) 5-2 Isomer 2: ethyl2-{4-[2- 2 and as (400 MHz, CDCl₃) δ: 1.24 (t, J = 7.0 Hz, 3 H), B m/z422 (M + H)⁺ (methoxycarbonyl)azepan- 190 1.28-2.14 (m, 20 H), 2.46-2.70(m, 2 H), 2.73-2.92 (ES+), at 5.54 min, 1-yl]piperidin-1-yl}-6- (m, 3H), 2.94-3.05 (m, 1 H), 3.21-3.46 (m, 4 H), UV activeazaspiro[3.4]octane-6- 3.52-3.61 (m, 1 H), 3.67 (s, 3 H), 4.06-4.16 (m,2 carboxylate H)

Biological Activity Example A

Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond. Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M₁, M₃ (Gq/11 coupled) and M₂, M₄receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M₁, M₂, M₃ or M₄ receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight. Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

The results are set out in Table 4 below.

For each example two diastereomers exist which have been separated,unless stated otherwise, and assigned based on their retention time onLCMS analytical trace. In most examples, isomer 1 is not active.Analytical data for active isomers is reported in Table 3. Data forseveral weakly active compounds are included in Table 4 to highlightpreference of absolute stereochemistry.

TABLE 4 Muscarinic Activity pEC₅₀ M₁ pEC₅₀ M₂ pEC₅₀ M₃ pEC₅₀ M₄ (% Emax(% Emax (% Emax (% Emax Ex. No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh8.3 (102) 7.8 (105) 8.1 (115) 8.1 (110) 1-1 Isomer 2 7.2 (121) <4.7 (20)<4.7 (26) 8.1 (112) 1-2 Isomer 2 6.6 (93) <4.7 (6) <4.7 (4) 7.6 (100 1-3Isomer 2 6.3 (30) NT NT 6.7 (41) 1-4 Isomer 2 6.0 (55) NT NT 6.6 (67)1-5 Isomer 2 6.9 (94) <4.7 (19) <4.7 (2) 7.7 (81) 1-6 Isomer 2 5.9 (128)<4.7 (57) *7.2 (38) 7.2 (71) 1-7 Isomer 2 6.8 (97) <4.7 (15) <4.7 (22)7.6 (97) 1-8 Isomer 2 6.5 (76) <4.7 (34) <4.7 (0) 7.8 (98) 1-9 Isomer 2<4.7 (57) NT NT 6.1 (48) 1-10 Isomer 2 5.3 (62) NT NT 6.6 (106) 1-11Isomer 2 5.8 (93) NT NT 6.6 (85) 1-12 Isomer 2 6.0 (85) <4.7 (11) <4.7(15) 6.9 (128) 1-13 Isomer 2 5.8 (61) NT NT 6.4 (86) 1-14 Isomer 2 6.2(66) <4.7 (27) <4.7 (5) 7.3 (99) 1-15 Isomer 2 7.0 (70) <4.7 (4) <4.7(6) NT 1-16 Isomer 2 5.8 (80) *5.1 (34) <4.7 (1) 6.8 (82) 1-17 Isomer 26.2 (53) <4.7 (14) <4.7 (0) 7.2 (90) 1-18 Isomer 2 6.9 (65) <4.7 (3)<4.7 (56) 7.3 (89) 1-19 Isomer 2 6.1 (83) NT NT *5.1 (48) 1-20 Mixtureof <4.7 (62) NT NT 6.0 (56) diastereorners 1-21 Isomer 2 <4.7 (11) <4.7(8) <4.7 (0) 7.4 (79) 1-22 Isomer 2 6.7 (47) NT NT <4.7 (20) 1-23 Isomer2 6.4 (55) <4.7 (7) <4.7 (9) 7.5 (105) 1-24 Isomer 2 6.6 (102) *5.2 (32)<4.7 (0) 7.6 (78) 1-25 Isomer 2 7.3 (110) <4.7 (15) <4.7 (13) 8.4 (128)1-26 Isomer 2 5.6 (46) <4.7 (99) 6.1 (53) 6.7 (76) 1-27 Isomer 2 6.0(27) NT NT 6.4 (41) 1-28 Isomer 2 5.7 (57) NT NT 6.3 (60) 1-29 Isomer 26.1 (44) NT NT 6.9 (36) 1-30 Isomer 2 6.5 (37) <4.7 (9) <4.7 (5) 7.9(101) 1-31 Isomer 2 5.6 (34) NT NT 7.0 (40) 1-32 Isomer 2 7.1 (113) <4.7(56) <4.7 (16) 8.2 (126) 1-33 Isomer 2 7.6 (11) 4.7 (49) <4.7 (7) 84(118) 1-34 Isomer 2 6.3 (49) <4.7 (10) <4.7 (0) 6.8 (48) 1-34 Isomer 28.1 (130) <4.7 (43) <4.7 (0) 8.6 (117) 1-35 Isomer 2 6.4 (80) NT NT 6.7(61) 1-36 Isomer 2 5.3 (73) NT NT 6.6 (47) 1-37 Isomer 2 5.6 (78) NT NT6.3 (126) 1-38 Isomer 2 7.0 (31) <4.7 (14) <4.7 (19) 6.1 (98) 1-39Isomer 2 6.0 (49) NT NT 6.4 (97) 1-40 Isomer 2 <4.7 (904) NT NT 6.8 (50)1-41 Isomer 2 6.0 (52) NT NT 6.6 (35) 1-42 Isomer 2 7.4 (123) 6.5 (27)<4.7 (16) 8.2 (76) 1-43 Isomer 2 6.8 (32) <4.7 (7) <4.7 (8) 7.5 (61)1-44 Isomer 2 7.1 (126) <4.7 (80) <4.7 (7) 8.2 (126) 1-45 Isomer 2 6.5(80) 5.8 (56) <4.7 (26) 7.7 (80) 1-46 Isomer 2 <4.7 (35) NT NT 6.7 (63)1-47 Isomer 2 <4.7 (7) 4.7 (82) <4.7 (19) 7.8 (81) 1-48 Isomer 2 <4.7(63) NT NT 6.2 (68) 1-49 Isomer 2 5.2 (71) <4.7 (21) <4.7 (9) 7.1 (92)1-50 Isomer 2 8.1 (124) <4.7 (20) <4.7 (8) 8.7 (122) 1-51 Isomer 2 5.9(74) NT NT 6.8 (106) 1-52 Isomer 2 6.8 (102) <4.7 (15) <4.7 (20) 7.8(106) 1-53 Isomer 2 5.3 (38) NT NT 5.9 (80) 1-54 Isomer 2 <4.7 (51) NTNT 6.1 (74) 1-55 Isomer 2 5.3 (40) NT NT 6.3 (64) 1-56 Isomer 2 6.0 (30)<4.7 (0) <4.7 (3) 6.9 (89) 1-57 Isomer 2 5.7 (63) <4.7 (7) <4.7 (7) 8.9(69) 1-58 Isomer 2 6.1 (55) <4.7 (13) <4.7 (2) 7.5 (93) 1-59 Isomer 26.4 (38) NT NT 7.0 (76) 1-60 Isomer 2 6.5 (82) NT NT 7.4 (88) 1-61Isomer 2 6.5 (66) <4.7 (1) <4.7 (2) 7.6 (97) 1-62 Isomer 2 5.9 (73) NTNT <4.7 (10) 1-83 Isomer 2 <4.7 (82) NT NT 6.0 (24) 1-64 Isomer 2 5.3(40) NT NT 6.5 (78) 1-65 Isomer 2 <4.7 (60) NT NT 6.6 (73) 1-66 Isomer 2<4.7 (14) NT NT 6.6 (32) 1-67 Isomer 2 5.5 (37) NT NT 6.5 (75) 1-68Isomer 2 7.1 91) NT NT 8.2 (98) 1-69 Isomer 2 7.1 (99) NT NT 8.3 (104)1-70 Isomer 2 7.1 (92) NT NT 8.3 (101) 1-71 Isomer 2 <4.7 (6) NT NT 7.0(69) 1-72 Isomer 2 <4.7 (17) NT NT 6.8 (69) 1-73 Isomer 2 <4.7 (11) NTNT 6.9 (72) 2-1 Isomer 2 <4.7 (6) <4.7 <4.7 6.5 (63) 2-2 Isomer 2 6.1(39) <4.7 (53) <4.7 (16) 7.2 (79) 2-3 Isomer 2 *5.0 (32) <4.7 (14) <4.7(4) 7.3 (89) 2-4 Isomer 2 6.5 (102) <4.7 (2) <4.7 (3) 7.3 (110) 2-5Isomer 2 *5.2 (34) NT NT 6.8 (66) 2-6 Isomer 2 5.5 (57) <4.7 (30) <4.7(16) 7.8 (132) 2-7 Isomer 2 6.1 (41) <4.7 (13) *5.1 (27) 7.9 (100) 2-8Isomer 2 6.2 (36) <4.7 (3) <4.7 (4) 7.8 (86) 2-9 Isomer 2 6.0 (43) <4.7(4) <4.7 (6) 8.0 (104) 2-10 Isomer 2 <4.7 (19) NT NT 6.7 (50) 2-11Isomer 2 *4.7 (39) <4.7 (7) <4.7 (7) 7.6 (100) 2-12 Isomer 2 <4.7 (9)<4.7 (9) <4.7 (6) 3.0 (57) 2-13 Isomer 2 *5.0 (69) <4.7 (7) <4.7 (24)6.8 (57) 2-14 Isomer 2 <4.7 (43) <4.7 (3) <4.7 (7) 7.8 (91) 2-15 Isomer2 6.4 (72) <4.7 (9) <4.7 (9) 7.8 (111) 2-16 Isomer 2 6.6 (41) <4.7 (53)<4.7 (7) 8.2 (114) 2-17 Isomer 2 6.7 (72) <4.7 (5) <4.7 (4) 8.5 (116)2-18 Isomer 2 <4.7 (8) <4.7 (1) <4.7 (4) 7.1 (56) 2-19 Isomer 2 6.2 (44)<4.7 (3) <4.7 (10) 8.1 (113) 2-20 Isomer 2 <4.7 (24) <4.7 (1) <4.7 (6)7.5 (106) 2-21 Isomer 2 6.2 (46) <4.7 (4) <4.7 (2) 8.1 (113) 2-22 Isomer2 <4.7 (7) NT NT 6.5 (31) 2-23 Isomer 2 5.9 (65) <4.7 (3) <4.7 (9) 7.3(104) 2-24 Isomer 2 6.2 (37) <4.7 (5) <4.7 (9) 7.7 (121) 2-25 Isomer 26.2 (74) <4.7 (6) <4.7 (2) 8.0 (86) 2-26 Isomer 2 *7.9 (92) <4.7 (66)<4.7 (4) 8.2 (99) 2-27 Isomer 2 *7.5 (24) <4.7 (0.4) <4.7 (15) 8.0 (73)2-28 Isomer 2 <4.7 (7) <4.7 (3) <4.7 (5) 7.6 (63) 2-29 Isomer 2 6.3 (60)<4.7 (5) <4.7 (13) 7.8 (110) 2-30 Isomer 2 6.3 (34) <4.7 (52) <4.7 (13)7.8 (97) 2-31 Isomer 2 6.9 (03) <4.7 (7) <4.7 (7) 8.5 (108) 2-32 Isomer2 5.6 (69) <4.7 (52) <4.7 (11) 7.9 (100) 2-33 Isomer 1 6.4 (86) <4.7 (8)<4.7 (3) 8.1 (109) 2-33 Isomer 2 <4.7 (4) <4.7 (5) <4.7 (5) 7.7 (65)2-34 Isomer 1 5.7 (74) <4.7 (16) <4.7 (8) 7.6 (89) 2-34 Isomer 2 5.5(56) <4.7 (3) <4.7 39) 6.6 (58) 2-35 Isomer 2 6.4 (108) <4.7 (1) <4.7(4) 7.8 (92) 2-36 Isomer 2 6.8 (89) <4.7 (3) <4.7 (5) 8.2 (113) 2-37Isomer 2 5.5 (106) <4.7 (33) <4.7 (58) 7.7 (83) 2-38 Isomer 2 6.8 (110)<4.7 (1) <4.7 (2) 8.3 (115) 2-39 Isomer 2 5.6 (41) <4.7 (1) <4.7 (1) 7.8(76) 2-40 Isomer 2 6.1 (78) <4.7 (2) <4.7 (1) 7.5 (90) 2-41 Isomer 2 5.6(36) NT NT 7.0 (91) 2-43 Isomer 2 *5.5 (19) <4.7 (4) <4.7 (5) 7.3 (47)2-44 Isomer 2 6.5 (71) <4.7 (4) <4.7 (8) 8.3 (100) 2-45 Isomer 2 6.6(67) <4.7 (5) <4.7 (5) 8.3 (111) 2-46 Isomer 2 *5.8 (32) <4.7 (5) <4.7(8) 7.8 (85) 2-47 Isomer 2 5.2 (45) NT NT 6.0 (63) 2-48 Isomer 2 6.5(34) <4.7 (3) <4.7 (5) 8.0 (81) 2-50 Isomer 2 6.6 (63) <4.7 (4) <4.7 (2)7.6 (73) 2-51 Isomer 2 <4.7 (237) <4.7 (1) <4.7 (3) 7.2 (53) 2-52 Isomer2 6.2 (49) <4.7 (4) <4.7 (4) 7.7 (85) 2-53 Isomer 2 7.1 (109) <4.7 (10)*5.2 (21) 8.1 (126) 2-54 Isomer 1 <4.7 (1) <4.7 (50) <4.7 (0) 7.8 (45)2-54 Isomer 2 7.3 (86) <4.7 (8) <4.7 (23) 8.9 (134) 2-55 Isomer 1 <4.7(15) NT NT 6.8 (67) 2-55 Isomer 4 <4.7 (7) <4.7 (22) <4.7 (12) 7.6 (52)2-56 Isomer 2 6.2 (96) <4.7 (8) <4.7 (0) 8.3 (134) 2-57 Isomer 2 <4.7(16) <4.7 (25) <4.7 (4) 7.5 (117) 2-58 Isomer 2 6.0 (66) <4.7 (45) <4.7(9) 7.5 (156) 2-59 Isomer 2 *5.5 (28) <4.7 (11) <4.7 (7) 6.6 (67) 2-61Isomer 2 <4.7 (10) NT NT 6.3 (40) 2-62 Isomer 2 <4.7 (20) <4.7 (6) <4.7(8) 7.8 (65) 2-63 Isomer 2 6.6 (34) <4.7 (0) <4.7 (4) 7.2 (60) 2-64Isomer 2 <4.7 (12) <4.7 (6) <4.7 (8) 8.5 (41) 2-65 Isomer 2 6.6 (60)<4.7 (1) <4.7 (1) 8.1 (107) 2-66 Isomer 2 7.4 (96) <4.7 (18) <4.7 (6)8.9 (115) 2-67 Isomer 2 <4.7 (19) <4.7 (67) <4.7 (1) 7.7 (79) 2-68Isomer 2 6.0 (32) <4.7 (4) <4.7 (6) 7.2 (73) 2-69 Isomer 2 6.4 (87) <4.7(3) <4.7 (2) 7.9 (110) 2-70 Isomer 1 5.4 (37) NT NT 6.8 (52) 2-70 Isomer2 5.8 (93) <4.7 (1) <4.7 (3) 7.5 (111) 2-71 Isomer 2 5.3 (39) NT NT 6.9(56) 2-72 Isomer 2 6.1 (30) <4.7 (13) <4.7 (10) 7.1 (52) 2-73 Isomer 2<4.7 (14) NT NT 6.5 (43) 2-74 Isomer 2 <4.7 (18) <4.7 (16) <4.7 (8) 7.1(54) 2-75 Isomer 2 6.5 (80) <4.7 (6) <4.7 (4) 8.6 (109) 2-76 Isomer 16.9 (82) <4.7 (10) <4.7 (35) 7.4 (114) 2-76 Isomer 2 7.3 (88) <4.7 (16)<4.7 (14) 7.9 (107) 2-77 Isomer 2 6.6 (51) <4.7 (14) <4.7 (47) 8.2 (105)2-78 Isomer 2 <4.7 (11) 4.9 (27) <4.7 (5) 6.9 (49) 2-79 Isomer 2 6.3(37) <4.7 (2) <4.7 (19) 7.5 (70) 2-80 Isomer 2 6.9 (98) <4.7 (16) <4.7(18) 7.7 (107) 2-81 Isomer 2 <4.7 (12) NT NT 7.2 (33) 2-82 Isomer 2 6.3(52) <4.7 (1) <4.7 (0) 7.7 (70) 2-83 Isomer 2 5.4 (55) NT NT 8.0 (100)2-84 Isomer 2 6.8 (36) <4.7 <4.7 7.7 (82) 2-85 Isomer 2 5.6 (66) NT NT<4.7 (3) 2-87 Isomer 2 6.4 (46) <4.7 (54) <4.7 (3) 7.8 (100) 2-88 Isomer2 6.5 (25) <4.7 (80) <4.7 (5) 7.4 (44) 2-89 Isomer 2 5.2 (37) <4.7 (68)<4.7 (8) 6.7 (102) 2-90 Isomer 2 6.8 (54) <4.7 (4) <4.7 (1) 7.9 (53)2-91 Isomer 2 6.3 (40) <4.7 (12) <4.7 (10) 7.1 (67) 2-92 Isomer 2 5.5(50) <4.7 (4) <4.7 (5) 7.5 (82) 2-93 Isomer 2 <4.7 (7) NT NT <4.7 (3)2-94 Isomer 2 <4.7 (7) NT NT 5.17 (80) 2-95 Isomer 2 <4.7 (19) <4.7 16)<4.7 (9) 7.2 (49) 2-96 Isomer 2 <4.7 (2) <4.7 (1) <4.7 (5) 6.9 (63) 2-97Isomer 2 <4.7 (5) <4.7 (3) <4.7 (3) 7.4 (37) 2-98 Isomer 2 <4.7 (10) NTNT 6.9 (45) 2-99 Isomer 2 <4.7 (18) NT NT 6.8 (54) 2-100 Isomer 2 <4.7(16) <4.7 (4) <4.7 (5) 6.7 (55) 2-101 Isomer 2 5.0 (70) NT NT 6.2 (98)2-102 Isomer 2 5.3 (23) <4.7 (1) <4.7 (11) 6.5 (45) 2-103 Isomer 2 6.7(26) <4.7 (4) <4.7 (3) 7.7 (100) 2-104 Isomer 2 7.1 (102) <4.7 (8) <4.7(8) 7.8 (111) 2-105 Isomer 2 <4.7 (26) NT NT 6.7 (38) 2-106 Isomer 2 6.9(97) <4,7 (10) <4.7 (5) 7.7 (102) 2-107 Isomer 2 7.2 (87) <4.7 (5) <4.7(46) 3.2 (92) 2-109 Isomer 2 6.4 (50) <4.7 (9) 5.0 (26) 7.8 (91) 2-109Isomer 4 6.5 (42) <4.7 (15) <4.7 (9) 7.7 (82) 2-111 Isomer 2 6.3 (31)<4.7 (1) <4.7 (0) 7.5 (62) 2-112 Isomer 2 <4.7 (7) NT NT 0.6 (63) 2-113Isomer 2 6.9 (100) NT NT 7.8 (113) 2-114 Isomer 2 6.9 (103) NT NT 8.1(114) 2-115 Isomer 2 6.7 (68) NT NT 7.6 (78) 2-116 Isomer 2 7.2 (109) NTNT 0.2 (103) 2-117 Isomer 2 5.2 (99) <4.7 (4) <4.7 (7) 7.2 (96) 2-118Isomer 2 <4.7 (33) NT NT 6.9 (84) 2-119 Isomer 2 5.6 (85) NT NT 6.9 (84)2-120 Isomer 2 6.4 (96) NT NT 6.5 (87) 2-121 Isomer 2 6.0 (31) NT NT 6.7(60) 2-122 Isomer 2 6.0 (59) NT NT 6.8 (60) 2-123 Isomer 2 6.5 (114)<4.7 (8) <4.7 (29) 6.5 (93) 2-124 Isomer 2 6.2 (45) <4.7 (2) <4.7 (0)7.1 (77) 2-125 Isomer 2 5.4 (32) NT NT 6.5 (81) 2-126 Isomer 2 <4.7 (15)NT NT 7.1 (60) 2-127 Isomer 2 <4.7 (11) NT NT 8.0 (72) 2-128 Isomer 25.0 (89) NT NT 5.8 (104) 2-129 Isomer 2 <4.7 (12) NT NT 7.0 (55) 2-130Isomer 1 6.5 (42) NT NT 7.9 (20) 2-130 Isomer 2 <4.7 (11) NT NT 7.2 (66)2-131 Isomer 2 6.3 (61) NT NT 6.8 (106) 2-132 Isomer 2 <4.7 (18) NT NT7.9 (72) 2-133 Isomer 1 <4.7 (37) NT NT 3.0 (70) 2-133 Isomer 2 7.1 (69)NT NT 9.2 (118) 2-134 Isomer 2 <4.7 (18) NT NT 7.2 (95) 2-135 Isomer 2<4.7 (15) NT NT 7.9 90) 2-136 Isomer 2 6.2 (105) NT NT 7.9 (110) 2-137Isomer 2 6.0 (78) NT NT 7.4 (111) 2-138 Isomer 2 <4.7 (17) NT NT 7.4(44) 3-2 Isomer 1 7.5 (97) <4.7 (7) <4.7 (0) 8.2 (115) 3-3 Isomer 2 7.6(81) *5.0 (0) <4.7 (56) 8.2 106) 3-5 Isomer 2 <4.7 (20) <4.7 (65) <4.7(11) 7.8 (80) 3-6 Isomer 2 <4.7 (74) <4.7 (0) <4.7 (4) 7.4 (58) 3-7Isomer 2 <4.7 (40) NT NT 1.0 (39) 3-8 Isomer 2 <4.7 (19) <4.7 (2) <4.7(0) 7.6 (54) 3-9 Isomer 2 6.6 (103) <4.7 (2) <4.7 (4) 7.6 (96) 3-10Isomer 1 5.9 (42) <4.7 (3) <4.7 (5) 7.1 (71) 3-10 Isomer 2 8.0 (90) 7.0(96) <4.7 (0) 8.9 (103) 3-11 Isomer 2 7.4 (36) NT NT 7.6 (58) 3-12Isomer 2 6.6 (34) <4.7 (2) <4.7 (5) 8.4 (110) 3-13 Isomer 2 7.9 (97)<4.7 (2) <4.7 (1) 7.9 (82) 3-14 Isomer 1 5.5 (65) NT NT 6.3 (65) 3-14Isomer 2 5.5 (29) NT NT 6.6 (75) 3-15 Isomer 2 6.6 (60) NT NT 7.4 (36)3-16 Isomer 2 5.1 (39) NT NT 5.6 (47) 4-1 Isomer 2 <4.7 (10) NT NT 7.16(47) 4-1 Isomer 4 6.4 (58) <4.7 (3) <4.7 (5) 7.3 (68) 4-2 Isomer 4 6.1(94) NT NT 7.1 (42) 4-3 Isomer 2 6.8 (103) <4.7 (9) <4.7 (4) 7.9 (88)4-4 Isomer 2 7.5 (97) <4.7 (19) <4.7 (21) 8.3 (73) 4-5 Isomer 2 6.3 (52)<4.7 (9) <4.7 (9) 7.8 (60) 4-6 Isomer 2 6.9 (66) <4.7 75 <4.7 (9) 7.377) 4-7 Isomer 2 5.4 (73) <4.7 (1) <4.7 (10) 6.8 (67) 4-8 Isomer 1 6.3(42) <4.7 (3) <4.7 (8) 7.2 (74) 4-10 Isomer 2 <4.7 (7) NT NT 6.6 (31)4-11 Isomer 2 <4.7 (54) NT NT 6.7 (55) 4-12 Isomer 2 <4.7 (19) <4.7 (7)<4.7 (14) 7.4 (32) 4-13 Isomer 2 6.2 (51) <4.7 (10) <4.7 (13) 7.0 (59)4-14 Isomer 2 6.7 (28) <4.7 (55) <4.7 (0) 7.7 (48) 4-15 Isomer 2 6.6(82) <4.7 (7) <4.7 (13) 7.2 (113) 4-16 Isomer 2 6.0 (94) NT NT 6.8 (1054-17 Isomer 2 <4.7 (27) NT NT 6.6 (106) 4-18 Isomer 2 5.5 (76) NT NT 6.2(79) 4-19 Isomer 2 <4.7 (7) NT NT 6.6 (38) 4-20 Isomer 2 <4.7 (11) NT NT6.8 (34) 5-2 Isomer 2 6.0 (58) <4.7 (5) <4.7 (4) 7.3 (96) *variableresults, NT—Not tested

Example B

Passive Avoidance

Studies were carried cut as described previously by Foley et al., (2004)Neuropsychopharmacology. In the passive avoidance task scopolamineadministration (1 mg/kg, i.p.) at 6 hours following training renderedanimals amnesia of the paradigm. A dose range of 3, 10, and 30 mg/kg(po) free base, administered 90 minutes prior to the training period viaoral gavage, was examined.

Example 1-33 Isomer 2 was found to reverse scopolamine-induced amnesiaof the paradigm in a dose-dependent manner, with an approximate ED₅₀ ofca. 10 mg/kg (po). The effect of 30 mg/kg was similar to that producedby the cholinesterase inhibitor donepezil (0.1 mg/kg, ip) which servedas a positive control (FIG. 1).

Example C

Effect of a Novel Test Compound and Xanomeline on d-Amphetamine-InducedHyperactivity in Rats

The aim of the study is to examine the effect of a novel test compoundon d-amphetamine induced hyperactivity in rats. Schizophrenia is acomplex multifactorial disease that cannot be fully represented by asingle experimental procedure. Antipsychotic-like behaviour was assessedin rats by the inhibition of hyperactivity (or hyperlocomotion) elicitedby d-amphetamine. This procedure is sensitive to clinically relevantdopamine receptor antagonists and is therefore considered suitable forcomparing muscarinic agonists that influence dopaminergic signalling. Adose of xanomeline previously observed to significantly reduced-amphetamine induced hyperactivity was employed as a positive control.Statistical analysis typically involved three-way analysis of covarianceor robust regression with treatment, day and rack as factors andactivity during the 30 minutes prior to treatment as a covariate,followed by appropriate multiple comparison tests. A P value of <0.05was considered statistically significant and is marked accordingly inaril subsequent figures.

Data for Examples 1-21 Isomer 2, 1-32 Isomer 2, 1-33 Isomer 2, 2-7Isomer 2 and 2-17 Isomer 2 is shown in FIG. 2.

Example D

Pharmaceutical Formulations

(i) Tablet Formulation

A tablet composition containing a compound of the formula (1), (1a) or(1b) is prepared by mixing 50 mg of the compound with 197 mg of lactose(BP) as diluent, and 3 mg magnesium stearate as a lubricant andcompressing to form a tablet in known manner.

(ii) Capsule Formulation A capsule formulation is prepared by mixing 100mg of a compound of the formula (1), (1a) or (1b) with 100 mg lactoseand optionally 1% by weight of magnesium stearate and filling theresulting mixture into standard opaque hard gelatin capsules.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

The invention claimed is:
 1. A compound of the formula (1b):

or a salt thereof, wherein Q is a five membered heterocyclic ringselected from the group consisting of:

R³ is selected from hydrogen; fluorine; cyano; hydroxy; amino; and aC₁₋₉ non-aromatic hydrocarbon group which is optionally substituted withone to six fluorine atoms and wherein one, two or three, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S and oxidized forms thereof; R⁴ is ahydrogen or a C₁₋₆ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof; and the dotted line indicates an optional second carbon-carbonbond, wherein R³ is present and the optional second carbon-carbon bondis absent.
 2. A compound according to claim 1 wherein R³ is selectedfrom hydrogen; fluorine; hydroxyl, methoxy and cyano.
 3. A compoundaccording to claim 1 wherein R⁴ is selected from hydrogen and methyl. 4.A pharmaceutically acceptable salt of a compound according to claim 1which is selected from the group consisting of: Ethyl2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4-chloro-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4,5-dichloro-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(ethoxycarbonyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4(1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3-amino-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,3-oxazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1,3-thiazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,3-thiazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(5-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,3,4-oxadiazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,2,4-thiadiazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-tetrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-pyrrol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4-methyl-1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-hydroxy-4-(1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-imidazol-2-yl)-4-methoxypiperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(4-methyl-1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4(1,2-oxazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3-methyl-1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(3-methyl-1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-ethyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1-propyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-propyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,3-thiazol-4-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;(2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)aceticacid; Ethyl2-(4-{1-[2-(methylamino)-2-oxoethyl]-1H-imidazol-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1,4-dimethyl-1H-pyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,4-dimethyl-1H-pyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1,4-dimethyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1,4-dimethyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2H-1,2,3-triazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1H-tetrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(5-methyl-1H-tetrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-methyl-1H-tetrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-ethyl-1H-tetrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2-ethyl-2H-tetrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;(1,1-²H₂)Ethyl2-[4(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;(2,2,2-²H₃)Ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;(²H₅)Ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;(1,1-²H₂)Ethyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;(2,2,2-²H₃)Ethyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate,and (²H₅)Ethyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.5. A pharmaceutically acceptable salt of a compound according to claim 1which is selected from the group consisting of: Ethyl2-[4-(pyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-formylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-acetylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(trifluoroacetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-[4-(1-propanoylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-propanoylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(cyclopropylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(cyclobutylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-{4-[1-(methoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(methoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(ethoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(ethylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(dimethylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(1-methylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(N-methylglycyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[1-(methoxycarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(propan-2-ylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2,2,2-trifluoroethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(azetidin-1-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(morpholin-4-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(cyclopropylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(cyclobutylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2-methoxyethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(pyrrolidin-1-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(methoxycarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[methoxy(methyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(1-methylcyclobutyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(3-methyloxetan-3-yl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(3,3-difluoropyrrolidin-1-yl)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(3,3-difluorocyclobutyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(3,3-difluoroazetidin-1-yl)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-(4-{(2S)-1-[(2,2,2-trifluoroethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-(4-{(2S)-1-[(3,3-difluoroazetidin-1-yl)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(cyclobutyloxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2-fluoroethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2,2-difluoroethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(methoxyacetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2-fluoroethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2,2,2-trifluoroethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(methylsulfanyl)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(2-methoxyethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-{[2-(dimethylamino)ethoxy]carbonyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(hydroxyacetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(pyridin-2-ylmethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[methyl(2,2,2-trifluoroethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(oxetan-3-ylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[methyl(oxetan-3-yl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-propanethioylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S,4S)-4-fluoro-1-propanoylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-4,4-difluoro-1-propanoylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-ethylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[methyl(pyridin-2-ylmethyl)carbamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[(pyridin-2-ylmethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-□-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(□-alanyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-{[2-(methylamino)ethoxy]carbonyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(2-fluoroethyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(2-methoxy-2-oxoethyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2S)-1-[2-(dimethylamino)-2-oxoethyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-benzylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(methylcarbamothioyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(methylcarbamoyl)-2,3-dihydro-1H-isoindol-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-phenylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Methyl2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(pyridin-4-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(pyrimidin-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(1,3-thiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(1,3,4-thiadiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,and Ethyl 2-{4-[(2S)-1-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.6. A pharmaceutically acceptable salt of a compound according to claim 1which is selected from the group consisting of: Ethyl2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;1-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidin-4-yl}-4,4-difluoro-D-proline;Ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(dimethylcarbamoyl)-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-carbamoyl-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxycarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-(4-{(2R)-4,4-difluoro-2-[methoxy(methyl)carbamoyl]pyrrolidin-1-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-4,4-difluoro-2-(methylcarbamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-(dimethylcarbamoyl)-4,4-difluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(methoxycarbonyl)-2-methylpyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(6-oxo-7-oxa-1-azaspiro[4.4]non-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4S)-4-(methoxycarbonyl)-1,3-thiazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(3R)-3-fluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(3S)-3-fluoropyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3,3-difluoropyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(fluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(difluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3-azabicyclo[3.1.0]hex-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-4,4-difluoro-2-methylpyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-4,4-difluoro-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2,5-dioxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2,2-dimethyl-5-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4R)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4R)-4-ethyl-2-oxo-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4R)-2-oxo-4-(propan-2-yl)-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4S)-4-ethyl-2-oxo-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(4S)-2-oxo-4-(propan-2-yl)-1,3-oxazolidin-3-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(2-oxoimidazolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-[4-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(1H-tetrazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(2-methyl-2H-tetrazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[2-(1-methyl-1H-tetrazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(thiophen-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R)-2-(1,3-thiazol-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R,4S)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;Ethyl2-{4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,and Ethyl2-{4-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate.7. A compound according to claim 1 which is ethyl2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 8. A compound according to claim 1 which is ethyl2-{4-[(2R,4S)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 9. A compound according to claim 1 which is ethyl2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 10. A compound according to claim 1 which is ethyl2-{4-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 11. A compound according to claim 1 which is ethyl2-{4-[(2R)-4,4-difluoro-2-(1-hydroxyethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 12. A compound according to claim 1 which is ethyl2-{4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 13. A compound according to claim 1 which is ethyl2-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 14. A compound according to claim 1 which is ethyl2-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 15. A compound according to claim 1 which is ethyl2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylateor a salt thereof.
 16. A method of treating Alzheimer's Disease,dementia with Lewy bodies or schizophrenia, comprising administering toa subject in need thereof an effective amount of a compound according toclaim 1.